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Keywords:

  • e-antigen;
  • hepatitis B;
  • pegylated interferon

Abstract

  1. Top of page
  2. Abstract
  3. Immunomodulatory therapy
  4. Conflicts of interest
  5. References

Worldwide, chronic hepatitis B virus infection is a major cause of end-stage liver disease and hepatocellular carcinoma. While the past two decades have brought major advances in the availability of treatments to help delay or prevent these outcomes, treatment of chronic hepatitis B remains a serious challenge. With the recent availability of potent new nucleot(s)ide such as entecavir, tenofovir and telbuvidine, I still use pegylated interferon (PEG-IFN)-α for the treatment of chronic HBeAg-positive patients. This is based on its relatively higher effectiveness in restoring the host immune control on viral replication, resulting in sustained diseases remission in a proportion of patients, a finite course of therapy and the absence of viral resistance. The two major hindrances to its wide application are its lack of effectiveness in a large proportion of patients and its side-effect profile. The former shortcoming can be circumvented to a certain extent with the use of response predictor models. Recently, based on long-term follow-up study, the better durability of sustained response further enhances the confidence in the use of PEG-IFN-α in chronic HBeAg-positive patients.


Immunomodulatory therapy

  1. Top of page
  2. Abstract
  3. Immunomodulatory therapy
  4. Conflicts of interest
  5. References

Interferon (IFN) has both antiviral and immunomodulatory properties. The aim of treatment with IFN is to induce a sustained response to treatment following a finite period of therapy. Conventional IFN has been largely superseded by pegylated interferon (PEG-IFN) because of its improved administration schedule (once weekly vs thrice weekly injection).

Pegylated interferon

With its improved pharmacokinetic profile and results of large multicentre trials (1, 2), conventional IFN has been dropped from treatment recommendations for chronic hepatitis B (CHB) management in favour of the pegylated form (3). A trial of PEG-IFN showed benefit over conventional IFN in patients with HBeAg-positive CHB following treatment for 24 weeks (4). Trials investigated the efficacy of PEG-IFN, with and without the addition of lamivudine, in comparison with lamivudine. In patients with HBeAg-positive disease, a 48-week course of PEG-IFN treatment produced significantly greater rates of seroconversion, suppression of hepatitis B virus (HBV) DNA replication and alanine aminotransferase (ALT) normalisation compared with lamivudine, as measured 24 weeks post-treatment. Despite providing greater on-treatment HBV DNA suppression, the addition of lamivudine to PEG-IFN did not produce any advantage in terms of response rate 24 weeks post-treatment compared with PEG-IFN monotherapy. Eight patients in each of the two PEG-IFN treatment arms achieved HBsAg seroconversion 6 months post-treatment cessation, an HBsAg seroconversion rate of 3 vs 0% for those treated with lamivudine alone. Longer-term follow-up of 172 patients treated with PEG-IFN monotherapy in the original study, of whom 69 (40%) had HBeAg seroconversion 6 months post-treatment, revealed that the response was sustained in 91% of this group, and that an additional 15% of patients developed a late serological response 6–12 months after ending therapy (5). Multivariate analysis indicated that response to PEG-IFN was associated with higher baseline ALT and lower HBV DNA and HBeAg level, but not with gender, age, race or body weight. Genotype A infection was associated with a better response (52%) compared with genotypes B (30%), C (31%) and D (22%). Long-term sustained HBeAg seroconversion was associated with substantial HBV DNA reduction and ALT normalisation, with 72% of patients having HBV DNA levels <10 000 copies/ml (∼2000 IU/ml) and 82% having normal ALT 1 year post-treatment. Studies of PEG-IFN α-2b with or without lamivudine for 1 year found that 35% of subjects had lost HBeAg at follow-up, that there was no benefit from the addition of lamivudine, and that genotype A subjects had a better response (6).

Predicting response to pegylated interferon

Baseline HBV DNA and ALT levels can be used to predict the likelihood of a response to PEG-IFN therapy in HBeAg-positive disease: patients with a low HBV DNA (≤10 log) and a high ALT level [>5 × upper limit of normal (ULN)] have a greater chance of response to PEG-IFN (50% chance of HBeAg seroconversion) than patients with high HBV DNA and lower ALT levels (7), and HBeAg quantification is a better predictor of HBeAg seroconversion than HBV DNA (8) but unfortunately this test is not yet commercially available.

Durability of response

Long-term follow-up studies in HBeAg-positive disease have shown that there are important differences between IFN-based and nucleos(t)ide analogue-based therapies (9). The data accumulated in the literature suggest that IFN-based therapy is able to induce a more long-lasting remission in patients with CHB compared with nucleos(t)ide analogue-based therapy. In addition, long-term studies of up to 11 years follow-up in patients with HBeAg-positive disease have shown that IFN therapy significantly reduces the risk of cirrhosis and hepatocellular carcinoma, while significantly increasing survival compared with matched untreated controls (10).

Towards a unified treatment management strategy

There are accumulating evidence for the efficacy of continuous nucleot(s)ide therapy, providing highly effective HBV suppression, ALT normalisation and improvement in liver histology. On the other hand, HBsAg seroconversion is rarely observed and, compared with IFN-based treatment, sustained, off-therapy response is less common where cessation is more often followed by relapse (10, 11).

With the availability of newer nucleos(t)ide analogues, we need to use these agents wisely and in patients where they are most likely to bring benefit. Both immunomodulatory and nucleos(t)ide analogue agents have their pros and cons (Table 1) and both find application in patient management – but the treatment strategy chosen must be one that considers all relevant factors for each individual patient and balances the potential benefits vs risks. Such factors include patient age, severity of liver disease, other comorbidities if relevant, preference and anticipated treatment duration. While nucleos(t)ide analogues are the only available treatment for a patient with decompensated cirrhosis (for whom IFN-based therapy would be contra-indicated), a course of PEG-IFN may be the most appropriate first-line treatment strategy in a young patient in order to give them a one in three overall chance of sustained response. If seroconversion is not achieved with PEG-IFN, longer-term treatment with nucleos(t)ide analogues could be a fall-back strategy. Patients who opt for a finite course of PEG-IFN must be made aware of the side effects they are likely to encounter while those choosing nucleos(t)ide analogue therapy must be made aware of the necessity for longer-term treatment as well as the risk of resistance development and its consequences.

Table 1.   Pros and cons of available treatment options
Nucleos(t)ide analoguesPegylated interferon
  1. HBV, hepatitis B virus.

Daily oral administrationWeekly subcutaneous injection
Potent HBV DNA suppressionLess potent HBV DNA suppression
Minimal side effectsFrequent side effects
Risk of resistance development on prolonged therapyNo resistance
No increase in HBsAg seroconversionIncrease, albeit low HBsAg seroconversion
Less durable off-treatment responseMore durable off-treatment response
Long-term therapy – potential for drug fatigueFinite therapy duration

Expense is a major consideration when selecting treatments and it is an unfortunate fact that not all patients have access to equivalent treatments. In many Asian and sub-Saharan countries, despite the high rate of resistance development, lamivudine is frequently prescribed as a result of the cost savings compared with other nucleos(t)ide analogues or IFN-based therapy. However, the higher initial cost of IFN-based treatments (3) may be considerably offset against the sustained off-treatment responses that have been observed, when compared with continuous on-treatment therapy with nucleos(t)ide analogues, wherein costs of potential combination therapy regimens may approach that of IFNs. While a recent analysis suggested that entecavir may be the most cost-effective strategy for HBeAg-positive patients over a 5-year perspective, its higher cost being offset by decreased progression of disease, long-term efficacy and low resistance rate remain unproven (12). Moreover, projection over a longer time span improved the cost-effectiveness of an IFN regimen, suggesting potential cost benefit particularly in younger individuals (13). The growing number of antiviral drugs both approved for use and in development may allow for effective management of CHB with either ‘add-on therapy’ or drug switching. However, with only the single viral target of the HBV DNA polymerase, the potential for development of cross-resistance becomes a real practical problem. Hence, careful planning of any nucleos(t)ide analogue-based regimen should be an essential element in CHB patient management, which will also require regular monitoring for sustained HBV DNA suppression and viral rebound and resistance. If HBV DNA does not decrease within 12–24 weeks of initiation of therapy, clinicians should add or change therapy as long-term viral suppression and HBeAg loss and seroconversion is uncommon and there is an increased risk of resistance (14, 15).

A basic algorithm to improve clinical outcomes is proposed in Figure 1. In appropriately selected patients, immunomodulatory therapy of finite duration with PEG-IFN or conventional IFN should be the first-line treatment of choice. For those who do not achieve sustained remission, treatment of longer duration with nucleos(t)ide analogues should be instigated as a second choice. However, nucleos(t)ide analogue therapy may be the treatment of choice for certain patient groups, such as the immunocompromised (16), those beginning chemotherapy (17), or pregnant with high HBV viral loads (>1000 million/copies/ml or ∼200 million/IU/ml) (18) or those unwilling to take IFN therapy. While the genotype appears to influence the rate of response to IFN therapies, with patients infected with HBV genotype A responding best, the infecting genotype has not yet been shown to have an effect on response to nucleos(t)ide analogues. Thus, genotype may play a role in selecting first-line therapy in areas where genotypes A or D are prevalent but does not influence therapeutic decision where genotypes B and C are common.

image

Figure 1.  Proposed treatment algorithm to improve clinical outcomes.

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As well as deciding how to treat patients, clinicians must also consider whether treatment is absolutely necessary, especially if resources are limited. Monitoring of patients, especially those with HBeAg-positive CHB without evidence of jaundice, every 3–6 months is important – they may not be in need of immediate treatment, because spontaneous HBeAg seroconversion can occur at a rate of ∼10% of patients per year.

However, defining strict indications for initiating CHB treatment is problematic, because of the frequently fluctuating nature of the disease; for example HBV DNA <1000 copies/ml (∼200 IU/ml) may indicate inactive disease, whereas >100 000 copies/ml (∼20 000 IU/ml) indicates active infection, but this level of HBV DNA accompanied by normal ALT and histology may indicate an immunotolerant carrier in a young person. Persistently elevated ALT levels, defined as ≥2 × ULN with HBV DNA >100 000 copies/ml (∼20 000 IU/ml) are accepted as strong evidence to start treatment (3, 19–22). Elevated ALT levels plus HBV DNA levels of 10 000–100 000 copies/ml (∼2000–20 000 IU/ml) have more recently been suggested as indications for treatment, but preliminary liver biopsy to establish moderate to severe inflammation or fibrosis is recommended before initiating therapy on a case-by-case basis (1, 23, 24).

Timing of treatment can influence the likelihood of response; high baseline levels of ALT are known to be predictive of response to treatment both with IFN-based and nucleos(t)ide analogue therapy (25, 26). Similarly, low baseline HBV DNA levels have also been associated with an improved rate of response to IFN-based therapy. A ‘watch and wait’ strategy may be preferable to initiating immediate treatment, particularly in young patients who may have many years of therapy ahead of them.

An important factor to remember when counselling patients in need of anti-HBV therapy is the likelihood of requirement for long-term therapy if nucleos(t)ide analogues are initiated. Currently there are no evidence-based recommendations regarding when to stop nucleos(t)ide analogue therapy should HBeAg seroconversion occur, although reports suggest that 6–12 months appears prudent. It is also worth bearing in mind that HBeAg loss, used as a measure of treatment success in many trials of nucleos(t)ide analogues is not as stringent an outcome as HBeAg seroconversion, which requires not only HBeAg loss but also development of the antibody to HBe. Although add-on use of nucleos(t)ide analogues may be necessary and beneficial in patients in whom the nucleos(t)ide analogue-resistant virus has developed, some experts suggest that de novo use of nucleos(t)ide analogues in combination should be used. A study by Yim et al. (27) found that mutations conferring resistance to multiple antiviral agents colocate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multidrug-resistant HBV; they conclude that de novo combination therapy may be required to prevent the emergence of multidrug-resistant mutants. Combination therapy with two nucleos(t)ide analogue drugs (lamivudine and tenofovir) has been suggested and has been shown to decrease the risk of resistance to lamivudine (28). The choice of combination will be important; for example, a Phase II study of lamivudine in combination with telbivudine showed that the combination was less effective than lamivudine alone, suggesting an antagonistic effect (29). Further studies are required to elucidate the long-term effects of resistance development (30).

In conclusion, a unified treatment strategy for the management of patients with CHB in order to make the best possible use of the resources currently available is required. Education, both of physicians and patients, is a key factor in combating CHB. Effective treatments for the management of CHB are available; the basic algorithm for their use suggested here should be regarded as an initial framework for further development.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Immunomodulatory therapy
  4. Conflicts of interest
  5. References

The author has not declared any conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Immunomodulatory therapy
  4. Conflicts of interest
  5. References