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Keywords:

  • chronic hepatitis B;
  • nucleos(t)ide analogues;
  • peginterferon;
  • prediction of response

Abstract

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References

Pegylated interferon-α (PEG-IFN) is still an important treatment option for both HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) patients even with the availability of potent nucleos(t)ide analogues (NUCs) with a low risk of resistance. The major advantages of PEG-IFN-based treatment include the limited duration of treatment and the good probability of achieving a sustained off-treatment response. Responders to PEG-IFN have an increased probability of HBsAg loss and survival. However, the limited number of patients who achieve a response and the high costs and side-effects associated with PEG-IFN limit its clinical use. The potent NUCs entecavir and tenofovir are therefore often used as a first-line treatment option. Unfortunately, the off-treatment durability of response to NUCs is generally low, requiring long-term continuous therapy. Recent progress making it possible to select patients with a high probability of achieving a response to PEG-IFN, and to adapt therapy early on in probable non-responders, should help further optimize the utilization of PEG-IFN in CHB.

Chronic hepatitis B (CHB) is a global health problem affecting more than 350 million people worldwide (1). Prolonged liver inflammation caused by infection with the hepatitis B virus (HBV) may ultimately result in the progression of liver inflammation to fibrosis, cirrhosis and ultimately hepatocellular carcinoma (HCC) and death (2).Current guidelines therefore recommend treating CHB in patients with active liver inflammation (1, 3). The introduction of nucleos(t)ide analogues (NUCs) has provided the hepatologist with novel treatment options, and NUCs have been shown to be a safe and effective alternative to interferon (IFN), at least in the short term. However, interest in IFN-based treatment regimens has been renewed after the introduction of pegylated interferon-α (PEG-IFN), which has better pharmacokinetic properties, a more convenient dosing regimen and probably greater antiviral potency than regular IFN (4). Current international guidelines recognize five NUCs for the treatment of CHB [lamivudine (LAM), telbivudine (LdT), adefovir (ADV), entecavir (ETV) and tenofovir (TDF)], along with two formulations of PEG-IFN (PEG-IFN α-2a and α-2b) (5). Recent multinational registration trials and subsequent follow-up studies have shown that third-generation NUCs (ETV and TDF) can effectively maintain the suppression of HBV DNA levels during prolonged therapy, with little or no risk of antiviral resistance. Why then should we still consider PEG-IFN for the treatment of CHB?

Treatment paradigms in chronic hepatitis B

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References

In contrast to chronic hepatitis C, the complete eradication of the HBV from host hepatocytes cannot be achieved with currently available agents, because of the persistence of HBV covalently closed circular DNA (cccDNA). The main goal of anti-HBV therapy is therefore to stop the progression of liver inflammation to fibrosis, cirrhosis or HCC (6). Because these outcomes may not develop until after decades of infection, surrogate outcome markers are used as endpoints for successful therapy.

Currently, the main endpoints are a reduction of HBV DNA to undetectable levels (virological response), loss of HBeAg with or without the appearance of anti-HBe (serological response), a reduction in alanine transaminase (ALT) to levels considered normal (biochemical response) and improved liver histology (7). Loss of HBsAg from serum, accompanied by the appearance of anti-HBs, is currently considered the optimal surrogate endpoint, although it is rarely achieved (8).

In HBeAg-positive CHB patients treated with (PEG-)IFN, loss of HBeAg accompanied by the appearance of anti-HBe (HBeAg seroconversion) is an important treatment endpoint, because it is associated with a high probability of subsequent HBsAg loss and increased survival (2, 5, 7, 9, 10). However, recent studies support the use of a combined serological and virological endpoint (HBeAg loss or seroconversion with concomitant HBV DNA<10 000 copies/ml), because this endpoint is associated with a low probability of relapse, a reduction in the risk of progression to HCC (11, 12) and a high probability of subsequent HBsAg loss (13). In patients treated with NUCs, the suppression of HBV DNA to undetectable levels for prolonged periods is often used as a treatment endpoint.

In HBeAg-negative CHB patients, prolonged suppression of HBV DNA to low (for PEG-IFN) or undetectable levels, combined with normalization of ALT, is currently considered the treatment goal of choice (5). One trial involving PEG-IFN used an HBV DNA level of <20 000 copies/ml combined with ALT normalization at 24 weeks post-treatment as a primary outcome measure (14), while several trials investigating the potency of NUCs used improvement in liver histology and HBV DNA undetectability (typically <300–400 copies/ml) as a primary outcome. Recent insight into the excellent prognosis of inactive HBV carriers has led to the use of these criteria [HBV DNA <2000 IU/ml (∼10 000 copies/ml) and ALT normalization] as response parameters for PEG-IFN therapy in HBeAg-negative CHB (15).

The disparities between treatment outcomes for NUCs and PEG-IFN therapy reflect an important difference in treatment approach: in patients treated with PEG-IFN, HBV DNA reduction is secondary to achieving immunological control over the virus (as measured using off-treatment sustained serological or combined serological and virological response). During treatment with NUCs, on-treatment maintained viral suppression to very low or undetectable levels is always essential, irrespective of achieving a virological response, for detectable HBV DNA is a risk factor for the emergence of viral resistance (3).

Peginterferon or nucleos(t)ide analogues?

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References

HBeAg-positive patients

Treatment indication

Current European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) guidelines recommend treatment for HBeAg-positive patients who present with levels of serum HBV DNA over 2000 IU/ml and/or with elevated ALT levels (>1 ULN for EASL, >2 ULN for AASLD). According to AASLD guidelines, patients with ALT between 1 and 2 ULN should be considered when liver biopsy shows at least moderate inflammation or fibrosis (5, 7).

Efficacy of peginterferon

After 1 year of treatment with PEG-IFN α-2a or α-2b, 25–27% of patients achieved HBeAg seroconversion (16, 17). Half a year after the discontinuation of treatment, this increased to 29–32%. Loss of HBsAg with the appearance of anti-HBs occurred in 4–6% of patients after 1 year of treatment and 6 months of post-treatment follow-up (16, 17). In both studies, the addition of LAM to PEG-IFN monotherapy did not increase serological response rates, although HBV DNA was more vigorously suppressed during treatment in patients who received combination therapy (16, 17). A representative cohort of 172 patients treated with PEG-IFN α-2b±LAM in the above-mentioned study were enrolled in a subsequent study and had one more follow-up visit at the local participating centre after a mean of 3 years. The long-term follow-up results are summarized in Figure 1A, both for the total cohort and for the subgroup of patients who were HBeAg negative at week 78 (18). Importantly, PEG-IFN-induced HBeAg loss was sustained in most cases, and HBsAg loss increased to 30% in patients who were HBeAg negative 6 months after treatment discontinuation (18).

image

Figure 1.  (A) Long-term follow-up (3 years) results of 172 HBeAg-positive patients treated with PEG-IFN α-2b±LAM for 1 year. Data are presented for the entire cohort and for the subgroup of patients who were HBeAg-negative 26 weeks after therapy discontinuation. (B) Long-term follow-up results of 315 HBeAg-negative patients treated with PEG-IFN α-2a, LAM or a combination for 1 year. Data are presented for the patients who received PEG-IFN vs those who were treated with LAM monotherapy. ALT, alanine transaminase; HBV, hepatitis B virus; LAM, lamivudine; PEG-IFN, peginterferon.

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Efficacy of nucleos(t)ide analogues

The five NUCs registered for CHB have all been evaluated in large registration trials, and considerable differences in antiviral potency were reported.

Lamivudine achieves the suppression of HBV DNA to undetectable levels in 40% of patients after 1 year of treatment (17), compared with 21% in ADV-treated patients (19), and 60% in patients treated with LdT (20). The newest NUCs, ETV and TDF, result in undetectable HBV DNA levels in 67 (21) and 76% (22) respectively. Because the inclusion criteria differed between studies, and head-to-head comparisons between most agents are lacking, these differences should be interpreted with caution. Nevertheless, HBeAg seroconversion rates were similar in all studies; approximately 20% of patients achieved HBeAg seroconversion after 1 year of NUCs-based treatment. However, recent studies have shown that it is unlikely that NUCs-induced HBeAg seroconversion confers immunological control over HBV comparable to that in PEG-IFN-treated patients or in those with spontaneous HBeAg seroconversion. The durability of remission after NUCs-induced HBeAg seroconversion is generally low, both in patients treated with LAM or the more recent NUCs (23–25). It is therefore likely that NUCs therapy should be prolonged indefinitely or until HBsAg seroconversion occurs.

During prolonged therapy, most patients treated with ETV and TDF maintain undetectable HBV DNA and after 3 years of continuous TDF, or up to 5 years of ETV, all but a few patients achieve undetectable HBV DNA (26–28). HBsAg seroconversion is rare during treatment with NUCs, between 0 and 2 % after 1 year of therapy, increasing to 8% after 3 years of TDF in HBeAg-positive patients (27).

HBeAg-negative patients

Treatment indication

After loss of HBeAg from serum, HBV DNA levels may remain elevated because of the presence of viral mutants. The most commonly encountered mutations are located within the precore and core promoter regions and prohibit or abolish the synthesis of HBeAg (2). Current EASL and AASLD guidelines propose active therapy of HBeAg-negative CHB patients who present with levels of serum HBV DNA over 2000 IU/ml (20 000 IU/ml for AASLD) and with elevated ALT levels (>1 ULN for EASL, >2 ULN for AASLD). Patients with ALT between 1 and 2 ULN should be considered for therapy when liver biopsy shows at least moderate inflammation or fibrosis, according to the AASLD guidelines (5).

Efficacy of peginterferon

The efficacy of PEG-IFN α-2a in HBeAg-negative CHB patients has been evaluated in several multicentre international studies. In the registration study, patients were randomized to receive PEG-IFN α-2a alone, LAM alone or a combination for 48 weeks. Patients were subsequently followed up for 24 weeks. The primary endpoint was sustained off-treatment suppression of HBV DNA levels to below 20 000 copies/ml and normalization of ALT after 24 weeks of post-treatment follow-up; the response was 36% for the PEG-IFN monotherapy group (14). Thirty-eight percent of patients treated with PEG-IFN had HBV DNA levels <10 000 copies/ml after 24 weeks of follow-up (the level below which the inactive carrier state is defined) (15). Similar to HBeAg-positive disease, the addition of LAM to PEG-IFN increased the probability of a response at the end of treatment, but this difference was not sustained during the follow-up phase (14). In another study, patients were randomized to receive PEG-IFN α-2a alone or in combination with ribavirin for 48 weeks. The response rates (HBV DNA <10 000 and normal ALT) after 24 weeks of post-treatment follow-up were similar in both groups (16–20%) (29).

Response to PEG-IFN in HBeAg-negative patients, defined as post-treatment sustained HBV DNA levels <10 000 copies/ml, is durable in up to 43% of patients after 3 years of follow-up. The results of HBeAg-negative patients 3 years after PEG-IFN discontinuation are summarized in Figure 1B (15).

Efficacy of nucleos(t)ide analogues

In other studies, 1 year of LAM treatment resulted in HBV DNA suppression to undetectable levels in 72% (21), ADV in 63% (22), LdT in 88% (20), ETV in 90% (21) and TDF in 93% (22). The durability of post-treatment response to NUCs is generally low in HBeAg-negative CHB: 24 weeks after treatment discontinuation, LAM-induced HBV DNA undetectability was sustained in only 7% (14) and relapse rates increased further during prolonged follow-up (7, 30). Despite the higher antiviral potency of ETV, HBV DNA suppression to undetectable levels is sustained in only 3% of patients after 24 weeks of post-treatment follow-up (31). Like in HBeAg-positive disease, indefinite NUCs therapy should be anticipated in HBeAg-negative patients, for HBsAg loss rates are extremely low (26).

Safety

The safety and tolerability profiles of PEG-IFN and NUCs depend largely on their mode of action. One year of PEG-IFN-based therapy is associated with considerable side-effects. The most frequently reported effects are a flu-like syndrome, headache, myalgia, fatigue and local reactions at the injection site (14, 16, 17). Hepatitis flares have been reported during PEG-IFN therapy, and these may result in hepatic decompensation (32–35). Interestingly, a recent study reports that host-induced flares in HBeAg-positive patients treated with PEG-IFN, which are characterized by elevations in ALT and a subsequent decline in HBV DNA levels, are associated with increased serological response rates. (35) PEG-IFN therapy is also associated with mild myelosuppressive effects, but PEG-IFN-induced neutropenia and thrombocytopenia result in clinically significant symptoms, such as major infections and bleeding, in only a select group of susceptible patients (36).

Conversely, most NUCs are associated with mild side effects. Theoretically, therapy with NUCs poses risks, for most inhibit not only viral polymerase enzymes but also host mitochondrial DNA polymerases (37). This may result in a rare clinical syndrome including lactic acidosis, neuropathy and myopathy (37). Fortunately, most NUCs have been shown to be safe during the first years of treatment. In a large randomized study, adverse events did not occur more frequently during LAM treatment than in placebo-treated patients (38), and the side-effect profile of ETV is indistinguishable from that of LAM (39). In contrast, ADV is known to be nephrotoxic in up to one-third of patients (40) and renal toxicity has also been described in patients treated with TDF, although the latter seems relatively safe during the first year of therapy (22). TDF has been used extensively in HIV-treatment and renal toxicity has been described, necessitating creatinine monitoring, especially during prolonged treatment (37).

Selecting patients for peginterferon and adapting treatment

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References

Despite the benefits associated with PEG-IFN-based therapy, the clinical utility of PEG-IFN is compromised by the limited number of patients who achieve a sustained response, and by the higher costs (at least during the first year) and more frequent side-effects when compared with NUCs-based treatment (Table 1) (41). Optimizing PEG-IFN therapy is therefore dependent on tilting the balance, both by selecting patients for PEG-IFN therapy who have the highest probability of response, and by modifying therapy in patients who do not respond adequately to treatment.

Table 1.   Advantages and disadvantages of peginterferon vs nucleos(t)ide analogues
PEG-IFNNUCs
  1. Pros and cons of peginterferon and nucleos(t)ide analogues for chronic hepatitis B.

  2. HBV, hepatitis B virus; PEG-IFN, pegylated interferon-α; NUCs, nucleos(t)ide analogues.

Weekly subcutaneous injectionDaily oral dosing
Frequent side-effectsGenerally well tolerated
Modest HBV DNA suppressionPotent and swift HBV DNA suppression
Increase in the rate of HBsAg lossLimited increase in the rate of HBsAg loss
Response durable after therapyResponse not durable after therapy
No antiviral resistanceRisk of antiviral resistance
Finite duration of therapyLong-term or indefinite therapy may be required if HBsAg loss is not achieved
CostlyLess expensive during the first year, possibly equally or more costly after prolonged therapy

HBeAg-positive patients

A recent study has pooled data from the two largest trials with PEG-IFN (n=721) (42). The multivariable baseline prediction model presented by the authors allows for individual prediction of sustained response to PEG-IFN based on HBV genotype, HBV DNA level, ALT, sex, age and previous treatment with IFN. An easy-to-use guide based on HBV DNA and ALT levels in combination with HBV genotype is shown in Table 2. Using the so-called PEG-IFN treatment index (http://www.liver-gi.nl/peg-ifn), the recommendations from Table 2 can be refined, allowing for individual response prediction. We advise considering patients for PEG-IFN if the baseline probability of response is more than 30%, for in these patients, the benefits can be considered to outweigh the costs (42).

Table 2.   Recommendations for considering HBeAg-positive patients for pegylated interferon-α
HBV genotypeConsider PEG-IFN in HBeAg-positive patients with:
  1. Recommendations are based on an average probability of a sustained off-treatment response (HBeAg loss and HBV DNA <2000 IU/mL 6 months after treatment) of more than 30%. Probabilities for individual patients may vary, depending on other characteristics (including age and sex and prior IFN treatment failure).

  2. ALT, alanine transaminase; HBV, hepatitis B virus; PEG-IFN, pegylated interferon-α.

AEither high ALT (≥2 × ULN) or low HBV DNA (≤9 log copies/mL)
B or CBoth high ALT (≥2 × ULN) and low HBV DNA (≤9 log copies/mL)
DPEG-IFN generally not recommended

On-treatment monitoring of viral replication may help optimize PEG-IFN treatment by allowing the early identification of non-responders (5). Using data from the PEG-IFN α-2a trial, Fried et al. (43) identified a relationship between on-treatment HBV DNA levels and HBeAg levels and subsequent treatment response (defined as HBeAg seroconversion 24 weeks post-treatment). Patients with HBV DNA levels below 5 log10 copies/ml at week 24 had a 53% probability of response, compared with a probability of only 14% in patients with HBV DNA>9 log10 copies/ml. (43) Nevertheless, the clinical utility of these findings is limited, because many future responders would be lost if all patients with HBV DNA>9 log10 copies/ml were discontinued (43). In contrast, patients with the lowest HBeAg levels at week 24 had a 52% probability of sustained HBeAg seroconversion, whereas only 4% of patients with the highest levels achieved a response (43).

Similar observations have been reported for serum HBsAg levels. Serum HBsAg levels correlate with intrahepatic cccDNA levels in HBeAg-positive patients (44–46), and low cccDNA levels are predictive of a sustained off-treatment response (47). On-treatment HBsAg decline may therefore reflect the efficacy of PEG-IFN in reducing intrahepatic cccDNA levels and consequently predict a sustained response (44, 45). In one study, patients with the highest HBsAg levels had the lowest probability of response, compared with a probability of >50% in patients with HBsAg levels <1500 IU/ml at week 12 or 24 of treatment (48). Additionally, a recent study has shown that HBeAg-positive patients who fail to achieve a decline in serum HBsAg levels from baseline to week 12 of therapy have a very low probability (<5%) of response, and can be discontinued ((49), Fig. 2A).

image

Figure 2.  (A) Stopping rule described for HBeAg-positive patients treated with PEG-IFN. Sustained response was defined as HBeAg loss and HBV DNA <10 000 copies/ml at 6 months post-treatment. (B) Stopping rule described for HBeAg-negative patients treated with PEG-IFN. Sustained response was defined as HBV DNA<10 000 copies/ml combined with ALT normalization at 6 months post-treatment. HBV, hepatitis B virus; NPV, negative predictive value; PEG-IFN, peginterferon; PPV, positive predictive value.

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HBeAg-negative patients

Currently, data on baseline predictors of response to PEG-IFN are limited in HBeAg-negative subjects. A post hoc analysis of 518 patients treated with PEG-IFN α-2a investigated the baseline factors associated with a combined response defined as HBV DNA levels <20 000 copies/ml combined with ALT normalization at 24 weeks post-treatment. Using a multivariable logistic regression model, younger age, female gender, higher baseline ALT and lower baseline HBV DNA levels were shown to be independently associated with a higher probability of achieving a sustained response (50). However, another recent study was unable to confirm the relationship between these variables and a sustained response (51).

On-treatment prediction of response to PEG-IFN in HBeAg-negative CHB is difficult. Preliminary data show that a decline in HBV DNA during therapy is associated with a treatment response (42). Additionally, several studies have now shown that, like in HBeAg-positive patients, sustained responders experience a more pronounced HBsAg decline than non-responders (51–53) One small study reported that patients who achieved a >0.5 log10 IU/ml decline in HBsAg levels after 12 weeks of treatment had an 89% probability of a sustained response, while patients who did not achieve this decline had a 90% probability of non-response (52). HBsAg decline at week 12 was recently used to formulate a stopping-rule for HBeAg-negative patients treated with PEG-IFN: patients who fail to achieve both a decline in HBsAg levels and a >2log10 decline in HBV DNA have 0% chance of achieving a response and can be discontinued (Fig. 2B) (51).

Conclusion

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References

Peginterferon remains an important treatment option for CHB, even in the current era of potent NUCs, with a low risk of resistance during the first years of therapy. The major advantages of PEG-IFN include its limited therapy duration, the considerable probability of achieving a sustained off-treatment response and the higher HBsAg loss rate compared with NUCs. However, the limited number of patients who achieve a response, and the high costs and side-effects associated with PEG-IFN limit its clinical use. Recent progress allowing pretreatment selection of patients with a high probability of achieving a response, and early therapy adaptation for probable non-responders, will help further optimize the use of PEG-IFN for CHB.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References

Harry Janssen received grants from and is a consultant for Bristol-Myers Squibb, Gilead, Novertis, Roche, Schlering Plough. Milan Sonneveld has declared no potential conflicts.

References

  1. Top of page
  2. Abstract
  3. Treatment paradigms in chronic hepatitis B
  4. Peginterferon or nucleos(t)ide analogues?
  5. Selecting patients for peginterferon and adapting treatment
  6. Conclusion
  7. Conflicts of interest
  8. References