Interferon: a finite course of antiviral treatment

The disease of chronic hepatitis B hinges on a balance between the virus and the host immune system. Clearance of hepatitis B virus (HBV) relies on the host immunity. On the other hand, liver necroinflammation and cirrhosis occurs when there is persistent, yet unsuccessful, immune clearance of the virus.1 Interferon is the first registered drug for the treatment of chronic hepatitis B. It is an immune modulator with weak antiviral property. Its main function is to augment the host immune clearance of the virus. Hence interferon works best when the host is in the immune clearance phase with elevated liver enzymes and low HBV DNA.2 One major advantage of interferon is the finite treatment course, which can potentially lead to sustained remission of disease in the subsequent decades.3 Long-term follow-up studies have confirmed a reduction in risk of liver-related complications, hepatocellular carcinoma and liver-related mortality among sustained interferon responders.4 ,5

Interferon treatment: how long is enough?

Since the mid-1980s, the standard duration of interferon has been 16–24 weeks. Although some evidence suggested that prolonged interferon to 32 weeks might improve the response,6 24 weeks was still the recommended duration for hepatitis B e antigen (HBeAg)-positive patients in regional guidelines.7 ,8 Early studies of peginterferon have used 32-week peginterferon, with or without lamivudine combination, with satisfactory results.9 ,10 In the pivotal of studies of peginterferon, all patients received 48–52 weeks of treatment.11–13 The standard treatment duration of peginterferon for chronic hepatitis B was then set to 48 weeks in both HBeAg-positive and HBeAg-negative patients.7 ,14 The evidence to support the use of 48-week over 24-week peginterferon was only available half a decade after its global registration for this indication.15 In this study (the NEPTUNE study), peginterferon α-2a at a standard dose of 180 mcg/week for 48 weeks was associated with a higher rate of HBeAg seroconversion and HBV DNA suppression than a lower dose (90 mcg/week) or a shorter duration of therapy (24 weeks). Nonetheless, with 48-week peginterferon treatment, approximately a third patients achieve a sustained response, which is usually defined as HBV DNA <2000–20 000 IU/ml with HBeAg seroconversion (in HBeAg-positive patients) 24–48 weeks post-treatment.16 The obvious next question is: will extension of peginterferon beyond 48 weeks further improve its clinical efficacy?

Can we extend peginterferon beyond 1 year?

In a pilot study in the USA, 13 HBeAg-negative patients were treated by peginterferon with or without lamivudine combination for 60 weeks.17 At 6 months after stopping treatment, 62% patients had HBV DNA <20 000 copies/ml (approximately 4000 IU/ml) with a >2 log reduction from baseline and 38% patients had undetectable HBV DNA by PCR. Although it is a small, uncontrolled pilot study, it has already raised the enthusiasm to study the extension of peginterferon beyond 48 weeks.

In Italy, Lampertico and colleagues have conducted a randomised study to compare 96-week versus 48-week peginterferon to treat HBeAg-negative, predominantly genotype D HBV infected patients.18 At the end of treatment, there was no difference in the proportion of patients with HBV DNA <2000 IU/ml between the 96-week (67.3%) and the 48-week (58.8%) groups (p=0.37). However, at 48 weeks post-treatment, significantly higher proportion of patients in the 96-week group (28.8%) than the 48-week group (11.8%) had HBV DNA <2000 IU/ml (p=0.03). Hepatitis B surface antigen (HBsAg) seroclearance was observed in 3 (5.8%) patients in the 96-week group but none in the 48-week group. This is the first time, in a controlled trial setting, that 96-week peginterferon is proved to improve the response among the difficult-to-treat genotype D HBV infected patients.

Who should receive extended peginterferon?

One problem of using peginterferon is its potential side effects. In the design of this Italian study, peginterferon α-2a was dosed at the standard 180 mcg/week for the first year, but the dose was reduced to 135 mcg/week in the second year.18 The reason was clearly to pre-empt the side effects on extended peginterferon treatment. Although there seemed to be no difference in the adverse events between the 96-week and 48-week groups, a 96-week course of peginterferon may not be appealing to all patients, considering the inconvenient route of administration, the side effects and the drug cost. Genotype D HBV is notoriously difficult to treat19 ,20 and a 96-week treatment course may be justifiable. However, for patients infected by other HBV genotypes, a reasonable proportion of patients can achieve a sustained response with 48-week treatment. In other words, one ought to select the right patient for extended peginterferon therapy.

Baseline clinical factors such as HBV genotype, HBV DNA and alanine aminotransferase levels can predict the response to 48-week peginterferon treatment in HBeAg-positive and HBeAg-negative patients.19 ,20 However, these factors have little value to guide the duration of therapy. Inadequate HBV DNA suppression during treatment can predict non-response, but the timing and cut-off values of HBV DNA levels are controversial among different reports.21–23 On-treatment HBeAg level seems to be a better predictor than HBV DNA in a post hoc analysis of the phase III study of peginterferon α-2a for HBeAg-positive chronic hepatitis B.21 Unfortunately, there is no commercial HBeAg quantification test available and this test is useless in HBeAg-negative patients. Recently, serum HBsAg quantification has emerged as a useful on-treatment predictor of response to peginterferon therapy.24 The change in serum HBsAg level can reflect the amount and transcription activity of the covalently closed circular DNA inside the liver, thus being an indirect marker of immune control induced by peginterferon.25 In HBeAg-positive patients, HBsAg <1500 IU/ml at week 12 and 24 can predict good response, while HBsAg >20 000 IU/ml predicts non-response. In HBeAg-negative patients, a >10% decline of HBsAg at week 12 and 24 predicts good response, while an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 predicts non-response.26

The use of on-treatment prediction by HBsAg level has raised the possibility of response-guided therapy. Non-response can be a stopping rule of peginterferon, and these patients can switch to oral antiviral drugs at week 12 or 24 if indicated. Up to date, there are no data on how one can improve the treatment efficacy of the intermediate on-treatment responders. Even among the good on-treatment responders, the chance of sustained response is approximately 50%.24 Numerous studies have shown that combination therapy of peginterferon with lamivudine or adefovir will not improve the sustained response over peginterferon monotherapy.16 ,27 In a German cohort, even with prolonged adefovir for 2 more years after the 48-week course of peginterferon and adefovir combination, it did not improve the clearance or further suppress the transcription of covalently closed circular DNA in the liver.28 In a recent study in China with two different regimes of peginterferon and entecavir combination for HBeAg-positive chronic hepatitis B, again, the combination therapy arms did not have any advantage over the peginterferon monotherapy arm in terms of HBeAg seroconversion or HBsAg seroclearance.29 A multi-centre, randomised study in China is underway investigating whether extending peginterferon to 72 weeks can improve the response among the HBeAg-positive patients with an intermediate on-treatment HBsAg response.30 With the promising results from the study by Lampertico and colleagues in Italy,18 a confirmative result of extended peginterferon in a response-guided therapy algorithm is eagerly awaited.

Looking into the future: individualised treatment

One further step ahead will be individualised tailoring of peginterferon treatment duration according to the on-treatment response. A group of investigators in China have investigated the use of on-treatment HBV DNA decline to guide the treatment duration of conventional interferon in HBeAg-positive chronic hepatitis B patients.31 In the HBV DNA guided therapy group, interferon-α was continued until the HBV DNA level ceased to decrease by 1 log copies/ml at a 2-monthly interval, and these patients received a median of 10 (range 2–24) months of interferon. Compared with those who received a standard 6-month interferon treatment, the HBV DNA guided therapy group has a significantly higher sustained response than the standard therapy group up to 40 months post-treatment.

As serum HBsAg level can better reflect the immune clearance by peginterferon than HBV DNA, it is a very logical tool for the tailoring of treatment duration. In a post hoc analysis of a cohort of HBeAg-positive patients who received 48-week peginterferon, a low end-of-treatment (week 48) HBsAg level was associated with a higher chance of sustained response (defined as HBeAg seroconversion and HBV DNA <2000 IU/ml 6 months post-treatment).32 HBeAg seroconversion plus an HBsAg <1000 IU/ml at the end of treatment was associated with approximately 80% chance of sustained response. In fact, among untreated HBeAg-negative carriers with low HBV DNA, HBsAg <1000 IU/ml is associated with inactive hepatitis,33 higher chance of spontaneous HBsAg seroclearance34 ,35 and lower risk of hepatocellular carcinoma.36 ,37 Thus, a low HBsAg level together with a low HBV DNA level is likely reflecting a status of good immune control, no matter it is achieved spontaneously or induced by peginterferon therapy. It will therefore be interesting to study the role of serial on-treatment HBsAg monitoring, with or without HBV DNA, to tailor the duration of peginterferon therapy at an individual basis.

CONCLUSION

In the era of very potent oral antiviral agents with minimal risk of drug resistance, peginterferon still has a clinical role for its finite duration of therapy. The response to peginterferon tends to be very sustained years after stopping treatment.38 Lampertico and colleagues have opened up the possibility of improving peginterferon response by extending the treatment duration from 48 to 96 weeks.18 However, long-term peginterferon treatment is definitely not welcome by both patients and physicians. A careful selection of patients for extended peginterferon therapy is needed to strike the fine balance between treatment benefit and patient tolerance to the treatment. In future, one may need to select the right patient to treat at baseline, use response-guided therapy to avoid overtreating the non-responders and tailor the treatment duration according to the individual patient response during peginterferon therapy (figure 1).

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Figure 1

Proposed future strategy of using peginterferon to treat chronic hepatitis B. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; NA, nucleot(s)ide analogue; qHBsAg, hepatitis B surface antigen quantification.