Chronic Hepatitis B

A Treatment Update

Vincent Wong, MD; Henry Chan, MD

Disclosures

Semin Liver Dis. 2013;33(2):122-129. 

In This Article

Peginterferon

Current Evidence and Recommendations

Both conventional interferon and peginterferon are recommended as options for finite duration of treatment in chronic hepatitis B.[12–14] Conventional interferon is dosed at 5 to 10 MU three times weekly for 4 to 6 months in HBeAg-positive patients. The data for extended conventional interferon in HBeAg-positive patients is scanty, though there is some data suggesting that prolonging the treatment duration to 32 weeks may improve response rate.[15] As HBeAg-negative patients are generally having a lower sustained response rate, a 12-month course of interferon is usually recommended.

The major benefit of peginterferon over conventional interferon is a more convenient once weekly dosing. A phase II, dose ranging, multicenter study has shown superior efficacy of 6-month peginterferon alfa-2a over conventional interferon in HBeAg-positive patients.[16] However, another study in China comparing 6-month peginterferon alfa-2b versus conventional interferon only showed better response with peginterferon among genotype B HBV-infected patients and patients younger than 25 years old.[17] The recommended standard dose of peginterferon alfa-2a is 180 μg weekly for 48 weeks, which is the regime used in all the pivotal studies for both HBeAg-positive and HBeAg-negative patients.[18,19] It takes half a decade before the evidence to support the use of 48-week over 24-week peginterferon is available.[20] In this study (the Nephrotic Syndrome Study Network [NEPTUNE]), peginterferon alfa-2a at a standard dose of 180 μg/wk for 48 weeks was associated with higher rate of HBeAg seroconversion and HBV DNA suppression than a lower dose (90 μg/wk) or a shorter duration of therapy (24 wk).

The recommended dosing of peginterferon alfa-2b is 1.5 μg/kg weekly or 12 months, though the dosing and duration of peginterferon alfa-2b are variable in different studies.[17,21,22] In the multicenter, European study, peginterferon alfa-2b was started with 1.5 μg/kg weekly for 32 weeks, and the dose was reduced to 1.0 μg/kg weekly for the subsequent 20 weeks.[21] More evidence is required to document the optimal dosing of peginterferon alfa-2b in chronic hepatitis B.

Baseline Predictors of Response

Many baseline factors have been investigated to predict response to interferon therapy. In a combined analysis of 542 patients in three pivotal studies using both peginterferon alfa-2a and 2b, HBeAg-positive patients, a combination of HBV genotype, HBV DNA, and ALT levels can predict the chance of response to a standard 12-month peginterferon therapy.[23] Genotype A HBV infection has the best response; patients who have either baseline HBV DNA < 9 log copies/mL or ALT > 2 time upper limit of normal will have a > 30% chance of sustained HBeAg seroconversion. Genotype B and C HBV infections have similar intermediate response; patients need to have both baseline HBV DNA < 9 log copies/mL and ALT > 2 time upper limit of normal before they have a > 30% chance of sustained HBeAg seroconversion. Genotype D HBV is the most difficult to treat and cannot achieve 30% sustained response regardless of the baseline HBV DNA and ALT levels. Similarly, in HBeAg-negative patients, baseline HBV genotype, HBV DNA, and ALT levels can predict the response to 48-week peginterferon treatment.[24] Some early evidence suggested that host factor such as polymorphism near the IL28Bgene can predict response to peginterferon therapy, but more data are needed for confirmation.[25]

On-treatment Predictor of Response

Baseline predictors can only guide the selection of potential good responders for peginterferon treatment. However, they have little value to guide the duration of therapy once treatment is started. As peginterferon therapy involves subcutaneous injection and has many side effects, it is desirable if nonresponders are identified so that peginterferon can be stopped early. In other words, a stopping rule can reduce the unnecessary extension of peginterferon therapy in the nonresponding patients.

Patients who have inadequate HBV DNA suppression during the early phase of treatment usually respond poorly to peginterferon. However, the timing and cutoff values of HBV DNA levels are controversial among different studies.[26,27,28] In a post hoc analysis of the phase III study of peginterferon alfa-2a for HBeAg-positive chronic hepatitis B, an HBeAg level of > 100 PEIU/mL at week 24 has a 96% negative predictive value (NPV) for HBeAg seroconversion 24 weeks posttreatment.[26] Unfortunately, the results of this study have not been validated by other investigators, and HBeAg quantification is not useful in HBeAg-negative patients.

Serum HBsAg level is often used as an indirect marker of the level and transcriptional activity of the covalently closed circular DNA in the liver.[29] Pretreatment serum HBsAg level has some correlation with peginterferon response, but it may not be good enough as a standalone marker for patient selection. Responders to peginterferon usually have a more dramatic reduction in serum HBsAg level during treatment. In general, the greater reduction of serum HBsAg to lower level during treatment, the higher the chance of sustained response posttreatment. Based on the phase III study of peginterferon alfa-2a, HBsAg < 1,500 IU/mL at week 12 and 24 can predict an > 50% chance of sustained HBeAg seroconversion while HBsAg >20,000 IU/mL has a high NPV for nonresponse.[30] For HBeAg-negative patients, the best validated rule for nonresponse is an absence of HBsAg decline together with a < 2 log reduction in HBV DNA at week 12 in genotype D HBV infected patients, but more studies are required before it can be generalized to other HBV genotypes.[31] A > 10% decline of serum HBsAg level at week 12 and 24 can also predict a close to 50% chance of sustained response in HBeAg-negative patients.[32]

Response-guided Therapy

On-treatment HBsAg levels can be used as the backbone of response-guided therapy with peginterferon. Among patients who are likely nonresponders, peginterferon can be stopped at week 12 or week 24. If clinically indicated, nonresponders to peginterferon can be switched to oral antiviral drugs.

For patients with good or intermediate on-treatment HBsAg response, the strategy of response-guided therapy is not certain at the present moment. Continuation of peginterferon for the rest of the year will be a standard strategy. Based on the experience of lamivudine, adefovir and entecavir combination, adding an oral antiviral drug to peginterferon is unlikely able to improve the off-treatment response.[33–35] In a German cohort, even with prolonged adefovir for 2 more years after the 48-week course of peginterferon and adefovir combination, it could not improve the clearance or further suppress the transcription of covalently closed circular DNA in the liver.[36]

On the other hand, there is emerging evidence that extension of peginterferon for over 1 year may improve the sustained response and reduce the posttreatment relapse rate. A pilot study including 13 American HBeAg-negative patients treated with peginterferon for 60 weeks has resulted in a 62% virological response (defined as HBV DNA < 20,000 copies/mL with a > 2 log reduction from baseline) and 38% of undetectable HBV DNA at 6 months posttreatment.[37] Recently, an Italian randomized study among predominantly genotype D HBV infected HBeAg-negative patients has shown a significant higher rate of sustained virological suppression with 96-week versus 48-week peginterferon therapy. At 48-weeks posttreatment, 28.8% patients who received 96-week peginterferon and 11.8% patients who received 48-week treatment could achieve HBV DNA < 2,000 IU/mL.[38] Future randomized, controlled studies on the use of extended peginterferon therapy among patients with good or intermediate on-treatment response are awaited.

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