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Keywords:

  • HBeAg-negative;
  • hepatitis B;
  • PEG-IFNα sustained response

Abstract

  1. Top of page
  2. Abstract
  3. Pegylated interferon: registration trials
  4. How to improve a sustained response to interferon
  5. Conclusions
  6. Conflicts of interest
  7. References

Serum HBeAg-negative chronic hepatitis B, which is usually a late stage of chronic hepatitis B virus infection, is difficult to treat, because it is characterized by fluctuating alanine transaminase values resulting in hepatitis flares, accelerated progression to cirrhosis and liver cancer. Antiviral treatment, either long-term nucleot(s)ide therapy or 1-year administration of pegylated interferon (PEG-IFN), is therefore necessary to limit the course of the disease. A sustained virological response to PEG-IFN is achieved in approximately 1/4 of the patients, with significant rates of HBsAg seroclearance. While waiting for the results of several studies whose goal is to improve the long-term efficacy of PEG-IFN, the treatment strategy can be optimized by a careful selection of patients, discontinuation of PEG-IFN as early as possible in primary non-responders and extended therapy (up to 96 weeks) in responders.

The goal of antiviral therapy for chronic hepatitis B (CHB) is to improve the patient's quality of life and survival by preventing progression to cirrhosis, end-stage liver disease, liver cancer [hepatocellular carcinoma (HCC)] and liver-related death. This goal can be achieved by sustained or maintained hepatitis B virus (HBV) suppression either with short-term ‘curative’ treatment using standard interferon (IFN) or pegylated interferon (PEG-IFN) or a long-term ‘suppressive’ therapy with potent nucleot(s)ide analogues (NUCs) with high resistance barriers such as entecavir and tenofovir. The aim of the IFN-based strategy is to obtain a sustained virological response (SVS) and seroconversion to anti-HBs by a dual mechanism of action based on immunomodulation and antiviral activity. Patients with SVS have a higher probability of HBsAg seroclearance, a lower incidence of events (liver failure and HCC) and significantly better complication-free survival than non-responders. The advantage of PEG-IFN is that it induces durable suppression of viral replication in a significant percentage of patients following a limited duration of therapy. However, its disadvantages include parenteral administration, side effects and limited applicability.

In the therapeutic paradigm of CHB, all patients do not need to receive antiviral therapy because only patients at risk of progressing to advanced liver disease should be considered for treatment (1–3). Inactive carriers, i.e. anti-HBe seropositive patients with persistently normal alanine transaminase (ALT) levels and low serum HBV DNA (<2000 IU/ml), and patients with minimally elevated ALT levels and mild histological lesions, i.e. less than grade A2 or stage F2 by the METAVIR score, do not require treatment. According to EASL recommendations (3), HBeAg-negative patients are considered for treatment when HBV DNA levels exceed 2000 IU/ml, serum ALT levels are above the upper limit of normal and/or a liver biopsy (or eventually non-invasive markers when validated in HBV patients) shows moderate to severe active necro-inflammation and/or fibrosis using a standardized scoring system (at least grade A2 or stage F2 on the METAVIR score). Indications for treatment must also take into account age, health status and access to the expensive antiviral agents. Current guidelines recommend that patients with compensated cirrhosis and any detectable serum HBV DNA levels receive antiviral treatment regardless of ALT, while decompensated patients require urgent treatment with NUCs to obtain rapid inhibition of viral replication.

The primary objective of treatment with PEG-IFN is inducing the so-called ‘immune control’ status, characterized by persistent suppression of viral replication (serum HBV DNA levels <2000 IU/ml) and normalization of ALT levels, i.e. to revert the patient to an ‘inactive carrier’ state. If this condition is maintained over time, it increases the chances of HBsAg seroclearance and reduces the progression of fibrosis, thus preventing the development of end-stage liver disease and HCC, to ultimately increase survival (4–13).

Pegylated interferon: registration trials

  1. Top of page
  2. Abstract
  3. Pegylated interferon: registration trials
  4. How to improve a sustained response to interferon
  5. Conclusions
  6. Conflicts of interest
  7. References

A large multinational registration trial compared the long-term virological and biochemical response after 48 weeks of PEG-IFNα-2a (180 μg/week)±lamivudine (LMV) with LMV monotherapy alone (14). The combination of PEG-IFNα-2a and LMV led to a more profound, but transient, end of treatment virological response than PEG-IFNα-2a alone (92 vs 81%). Six months after treatment cessation, the response rate declined to 43 and 44% respectively. Long-term follow-up of 230 of the patients treated with PEG-IFN±LMV showed a sustained response in 21%, and HBsAg seroclearance in 12%, with 35% of sustained responders achieving this end point 5 years after the end of PEG-IFN±LMV treatment (15, 16) (Figs 1 and 2).

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Figure 1.  Sustained post-treatment virological response (HBV DNA <2000 IU/ml) after treatment with pegylated interferon with or without lamivudine in 230 patients with HBeAg-negative chronic hepatitis.

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image

Figure 2.  Progressive increase of HBsAg loss rates after the end of treatment with pegylated interferon with or without lamivudine in 230 patients with HBeAg-negative chronic hepatitis.

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How to improve a sustained response to interferon

  1. Top of page
  2. Abstract
  3. Pegylated interferon: registration trials
  4. How to improve a sustained response to interferon
  5. Conclusions
  6. Conflicts of interest
  7. References

Because of the limited long-term efficacy (20–30%) of a 48-week course of PEG-IFN, several approaches have been suggested to improve the virological and serological responses in patients with HBeAg-negative CHB.

Combination therapy with analogues

Although the combination of IFN and LMV is known to reduce the occurrence of LMV resistance (17, 18), there is no proof that this combination is better than monotherapy, except in patients infected with HBV genotype D (19). An Italian multicentre study evaluating the efficacy of a 48-week combination of PEG-IFN+adefovir dipivoxil compared with PEG-IFN alone showed similar rates of SVR 6 months after the end of therapy (23 vs 20%) (20). Similar results were obtained in a recent study comparing PEG-IFN+ribavirin (1000 or 1200 mg daily, depending on body weight) vs PEG-IFN plus placebo for 48 weeks. The 6-month off therapy combined biochemical and virological responses were similar between the two groups (20 vs 16%), while more episodes of anaemia and neutropenia were reported in the combination therapy group, suggesting that the addition of ribavirin did not improve response to therapy (21). Currently, guidelines do not recommend the use of PEG-IFN in combination with NUCs, but there are several ongoing studies to assess whether this combination is beneficial.

Extended duration of pegylated interferon administration

Based on the results testing the administration of standard IFN for more than 48 weeks to increase SVR rates by reducing the risk of relapse (22), a similar approach was tested with PEG-IFN.

In an American pilot study, seven patients with HBeAg-negative CHB received PEG-IFNα-2a (180 μg/week) for 60 weeks and six patients received PEG-IFNα-2a (180 μg/week) for 12 weeks, followed by 48 weeks of PEG-IFNα-2a+LMV. A SVR, defined as a ≥2 log10 copies/ml reduction of serum HBV DNA and <20 000 copies/ml of HBV DNA at 24 weeks of follow-up, was achieved in nine patients. Sixty weeks of PEG-IFN with or without LMV resulted in a higher rate of SVR than historical controls with HBeAg-negative CHB receiving 48 weeks of PEG-IFN (23).

In an Italian multicentre study evaluating the efficacy and safety of extended therapy with PEG-IFNα-2a in genotype D, 128 HBeAg-negative patients (24), mean age 45 years, ALT levels>1.5 normal values and HBV DNA>20 000 IU/ml, were randomly assigned to PEG-IFNα-2a for 48 or 96 weeks of monotherapy (group A and B) or combination therapy with PEG-IFNα-2a+LMV for 48 weeks, followed by another 48 weeks of 135 μg/week PEG-IFNα-2a (total time 96 weeks, group C). At the end of treatment, the virological response rates (HBV DNA <2000 IU/ml) were similar in both groups (59% for group A and 67% for group B) while the virological response rates 1 year post-treatment were significantly higher in patients treated for 96 than in those treated for 48 weeks (29 vs 12%, P=0.03) (Fig. 3). Three patients in group B and none of those treated in group A became HBsAg negative (6 vs 0%), while two additional patients in group B had <10 IU/ml HBsAg levels at the end of the study. Extended treatment was well tolerated and did not result in more adverse events or safety issues than in patients treated for 48 weeks. This study suggests that in difficult-to-treat HBeAg-negative patients, such as those infected with genotype D, PEG-IFN can be safely extended to 96 weeks, to increase the SVR to 30%.

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Figure 3.  Virological response rates (HBV DNA <2000 IU/ml) 6 and 12 months after treatment with pegylated interferon for 48 (group A) and 96 (group B) weeks in patients with HBeAg-negative chronic hepatitis.

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Baseline predictors of response

A subanalysis of patients treated with PEG-IFN with or without LMV identified baseline high ALT, low HBV DNA levels, female gender, younger age and HBV genotype as significant predictors of a combined response 24 weeks post-treatment (19). In the PEG-IFN monotherapy arm, patients with genotype B or C had a greater chance of response than genotype D-infected patients (P<0.001). The latter patients responded better to the combination than to PEG-IFN monotherapy (P=0.015). In general, the HBV genotype was a strong predictor of the 1-year post-treatment response independent of LMV administration.

On-treatment predictors of response

Five years ago, it became clear that serum HBV DNA was a poor on-treatment predictor of a sustained biochemical and virological response to PEG-IFNα-2a in HBeAg-negative CHB (25). In that study, however, ALT normalization rates and HBV DNA<20 000 copies/ml 24 weeks after the end of treatment were significantly higher in patients with HBV DNA<400 copies/ml at week 12 (70 and 61% respectively) than in those with HBV DNA ≥400 copies/ml (53 and 31%; P=0.023 and P<0.001) (25). In a French study of 48 HBeAg-negative CHB patients receiving PEG-IFNα-2a, the on-treatment viral kinetics in patients with initial viral suppression but subsequent relapse after stopping treatment were almost identical to patients achieving SVR (26). On the other hand, HBsAg kinetics during treatment was a significant predictor of a SVR, because a decrease of 0.5 and 1 log10 IU/ml of serum HBsAg levels at weeks 12 and 24 of therapy had a 90% negative predictive value (NPV) and an 89% positive predictive value (PPV) for week 12 and 97% NPV and a 92% PPV for week 24 analysis respectively. For the first time, early on-therapy virological and serological (HBsAg) responses have been shown to predict a sustained response. However, this study had several limitations such as a limited sample size, a retrospective study design, heterogeneous genotypes and a very strict definition of a virological response. Whether this algorithm can be applied to genotype D patients treated with PEG-IFN needs to be determined. In another study, Marcellin et al. (27) demonstrated that the absolute level of HBsAg during treatment is a better predictor of response: 37% of HBeAg-negative patients with ≤1500 IU/ml HBsAg levels at week 12 of PEG-IFNα-2a therapy with or without LMV showed clearance of HBsAg 4 years after treatment compared with 4% of those with HBsAg >1500 IU/ml (P<0.001). Brunetto et al. (28) showed that an end-of-treatment serum HBsAg level <10 UI/ml or an on-treatment reduction >2 log10 from baseline at week 48 was significantly associated with HBsAg loss after 3 years.

On-treatment stopping rule

Serum HBsAg levels were quantified at baseline, during treatment and at follow-up in 107 patients who participated in an international multicentre trial with PEG-IFNα-2a with or without ribavirin (29). From week 8 onwards, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in non-responders. The combination of HBsAg and HBV DNA decreases at week 12 of treatment was predictive of a SVR, because none of the 20 patients with unmodified HBsAg levels and a <2 log10 copies/ml decrease in HBV DNA levels had a long-term response (NPV=100%) (Fig. 4). This stopping rule has also been confirmed recently in patients treated with PEG-IFN for longer than 48 weeks, with the best results in genotype D patients (30). In a validation set of 160 patients (57% genotype D, 126 treated for 48 weeks and 34 for 96 weeks) SVR, i.e. HBV DNA<2000 IU/ml combined with normal ALT at 24 weeks of post-treatment follow-up, occurred in 57 (36%) patients. This stopping rule allowed treatment to be discontinued in 19% of patients while all sustained responders were kept on treatment. Also in the patients treated for 96 weeks, none of the seven (21%) with unmodified HBsAg levels and a <2 log10 HBV DNA decrease at week 12 achieved SVR.

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Figure 4.  Algorithm showing the chances of sustained response based on HBsAg decline and HBV DNA decline ≥2 log copies/ml at week 12 vs the baseline.

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These studies provide a rationale for stopping PEG-IFN at week 12 in approximately 20% of HBeAg-negative patients with a <2 log10 HBV DNA decrease and no change in HBsAg levels, because these patients have no chance of a response even after 48 weeks.

Conclusions

  1. Top of page
  2. Abstract
  3. Pegylated interferon: registration trials
  4. How to improve a sustained response to interferon
  5. Conclusions
  6. Conflicts of interest
  7. References

The treatment options for hepatitis B have been increased recently with the marketing of NUCs and PEG-IFN, leading to a significant improvement in the outcome of antiviral treatment. At the same time, the management of HBV patients has become more complex, requiring decisions on when to start antiviral treatment and which treatment should be started first. In this decision-making process, all relevant factors pertaining to the risks and benefits of treatment should be considered for each individual patient. When the purpose of treatment is to achieve a sustained response, a time-limited course of PEG-IFN may be the most appropriate first-line treatment strategy in young patients with mild disease, although the SVR to PEG-IFN in HBeAg-negative CHB are still not optimal. While awaiting the results of several ongoing studies on the optimization of this strategy, careful selection of eligible patients, early identification (week 12 on-therapy) of primary non-responders who can stop PEG-IFN and extending treatment beyond week 48 to reduce relapse rates may serve this purpose.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Pegylated interferon: registration trials
  4. How to improve a sustained response to interferon
  5. Conclusions
  6. Conflicts of interest
  7. References

Massimo Colombo receives a grant and research support from Schering-Plough, Roche, Gilead. He is on advisory committees and is a speaker and teacher for Bristol-Meyers-Squibb, Schering-Plough, Roche, Novartis, Gilead, Vertex.

Pietro Lampertico is on the advisory board and speakers bureau for Bristol-Meyers-Squibb, Roche, Novartis, Gilead, GSK.

Mauro Vigano has no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Pegylated interferon: registration trials
  4. How to improve a sustained response to interferon
  5. Conclusions
  6. Conflicts of interest
  7. References
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