Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues

doi:10.1016/j.bpg.2008.11.007

Best Practice & Research Clinical Gastroenterology

Volume 22, Issue 6, December 2008, Pages 1093-1108

https://doi.org/10.1016/j.bpg.2008.11.007 Get rights and content

The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30–35% of HBeAg-positive patients and 20–25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3–4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.

Section snippets

Practice guidelines for the treatment of chronic hepatitis B

The added complexity of treating chronic hepatitis B has led to the development of multiple national and international guidelines for the treatment of chronic HBV infection in the past few years, including the new guidelines of the European Association for the Study of the Liver (EASL) (http://www.act-hbv.com/guidelines/assets/EASL.pdf).4, 6, 7, *8, 9 All of these guidelines have advocated IFN-based therapy as one of the potential first-line therapies for both HBeAg-positive and HBeAg-negative

Endpoints of antiviral therapy

The ultimate virological endpoint of antiviral therapy for chronic hepatitis B is clearance of hepatitis B surface antigen (HBsAg) and appearance of respective antibody (anti-HBs). However, since HBsAg seroconversion can be achieved in only a small proportion of patients, other surrogate endpoints of antiviral therapy have been chosen. These endpoints can generally be assessed after 1 year of treatment and are associated with favourable long-term outcome. The most important endpoints of

Interferon-based regimens for the treatment of chronic hepatitis B

Interferon was discovered as an antiviral agent during studies on virus interference in the late 1950s. There are multiple naturally occurring forms of IFN, including IFN-α which is produced by lymphocytes. IFNs are involved in the host's elimination or control of acute and chronic viral infections. The effects of IFN are predominantly immunoregulatory, but it also has limited direct antiviral effect on HBV.¹⁵ IFN-α inhibits viral replication and degrades viral components, it induces the

Discussion

With the licensing of PEG-IFN and an additional four nucleos(t)ide analogues for the treatment of chronic hepatitis B available in the last few years, choice of antiviral therapy has become more important and more complex at the same time. Both treatment with IFN-based therapy and nucleos(t)ide analogues has proven effective and can improve long-term outcome. In order to decide which drug should be used as first-line therapy in a specific patients, the pros and cons of the available drugs as

Conclusion

The choice of antiviral therapy has at the same time become more important and more complex in the past decade. Both IFN-based treatment and nucleos(t)ide analogue therapy have significantly improved. When aiming for sustained off-treatment response, PEG-IFN seems to be the drug of first choice in eligible patients because of its finite duration of therapy and the higher response rates compared to nucleos(t)ide analogues. Since the evidence for the influence of HBV genotype on choice of

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A Prospective Five-Year Follow-up After peg-Interferon Plus Nucleotide Analogue Treatment or no Treatment in HBeAg Negative Chronic Hepatitis B Patients
2022, Journal of Clinical and Experimental Hepatology
Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients.
HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 μg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time.
Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups.
This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.
Hepatitis B core related antigen in relation to intrahepatic and circulating viral markers, before and after combination therapy: HBcrAg in chronic hepatitis B
2021, Annals of Hepatology
Citation Excerpt :
We found that baseline HBcrAg-levels could not predict PEG-IFN/NA treatment outcome. Treatment with Peg-IFN leads to FC in around 3-5% of patients and 1-2% in NA-based therapies [24]. Due to these low FC-rates, investigating the predictive value of HBcrAg for FC can be challenging as seen in previous studies [25,26].
Covalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver biopsies. Hepatitis B core-related antigen (HBcrAg) levels in plasma/serum have been proposed to reflect intrahepatic cccDNA-levels and may therefore monitor treatment efficacy. This study aimed to validate the relationship between HBcrAg and other intrahepatic and circulating viral markers in CHB patients with high viral load, before and after combination treatment.
Plasma/serum levels of HBcrAg, HBsAg, HBV-DNA, and HBV pregenomic RNA (HBV-pgRNA), and intrahepatic cccDNA and HBV-DNA levels and fibrosis scores were measured in 89 CHB patients with HBV-DNA levels of >100,000 copies/mL (17,182 IU/mL). Measurements were done before and after a 48-week treatment with pegylated interferon alfa-2a and adefovir in a prospective study (ISRCTN77073364).
Baseline HBcrAg-values correlated strongly with intrahepatic cccDNA (ρ 0.77, p < 0.001), intrahepatic HBV-DNA (ρ 0.73, p < 0.001) and plasma/serum HBV-DNA (ρ 0.80, p < 0.001), HBV-pgRNA (ρ 0.80, p < 0.001), and to lesser extend HBsAg (ρ 0.56, p < 0.001). Baseline HBcrAg-levels could not predict functional cure (FC) but HBcrAg-levels declined more strongly in patients who developed FC or HBeAg-loss. Furthermore, most correlations persisted at the end of treatment and follow-up.
HBcrAg reflects cccDNA transcription activity more accurately than HBsAg and may replace HBV-DNA as a marker during future treatment regimens, especially when cccDNA transcription is targeted or nucleot(s)ide analogues are included in the treatment regime.
Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference<sup>‡</sup>
2020, Journal of Hepatology
Citation Excerpt :
There is still a need to better understand the mechanisms of action of IFN-α and the basis for the higher rates of response in genotype A and B infection. The drawbacks of IFN-α include the side effect profile and the relatively low response rate overall.20 The initial sensing of infection is mediated by these receptors; thus, they are a crucial element of the innate immune response.
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to ‘cure’ HBV. Agreement among the conference participants was reached on some key points. ‘Functional’ but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV ‘functional cure’, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Targeting the Achilles heel of the hepatitis B virus: A review of current treatments against covalently closed circular DNA
2015, Drug Discovery Today
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Recent studies have shown that PEG-IFN-α has a superior anti-HBV effect over standard IFN-α, because of its longer half-life, and is recommended as a first-line therapy provided that its use is restricted to patients with a high probability of a positive response [62]. Although NAs show higher antiviral potency in HBV treatment, PEG-IFN-α achieves a higher sustained response after discontinuation of therapy and lack of acquired HBV resistance [63]. The greater sustained off-treatment response is thought to be caused by a restoration of the immune control [64].
Chronic infection with hepatitis B virus (HBV) often leads to the development of liver cancer and cirrhosis, creating immense sociological, clinical and economic burdens worldwide. Although current anti-HBV medications manage to control the disease progression and help restore normal liver functions, they often fail to eliminate the virus completely. A major reason for this failure is the presence of a stable viral genome in the hepatocyte nucleus: the covalently closed circular DNA (cccDNA). Targeting HBV cccDNA is a promising approach that could lead to a complete cure. Here, we review various research approaches that are directed toward eliminating HBV cccDNA. This is a brief, yet comprehensive, summary of current state-of-the-art developments in this emerging area of interest.
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Predictive factors for functional cure after sequential therapy with nucleos(t)ide analogues and pegylated interferon alfa -2b in treatment of chronic hepatitis B
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7Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues

Section snippets

Practice guidelines for the treatment of chronic hepatitis B

Endpoints of antiviral therapy

Interferon-based regimens for the treatment of chronic hepatitis B

Discussion

Conclusion

Gastroenterology

Gastroenterology

Gastroenterology

Hepatology

J Hepatol

J Hepatol

Gastroenterology

Antiviral Res

Lancet

Lancet

J Hepatol

Lancet

Gastroenterology

Gastroenterology

Hepatology

J Hepatol

Hepatology

J Hepatol

Hepatology

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

J Hepatol

Hepatology

Hepatology

Gastroenterology

Hepatology

J Hepatol

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Hepatology

Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures

J Viral Hepat

Hepatitis B virus infection

N Engl J Med

Epidemiology and natural history of hepatitis B

Semin Liver Dis

EASL International Consensus Conference on Hepatitis B. 13–14 September, 2002 Geneva, Switzerland. Consensus statement (long version)

J Hepatol

Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B

J Viral Hepat

The German guideline for the management of hepatitis B virus infection: short version

J Viral Hepat

Asian-Pacific consensus statement on the management of chronic hepatitis B

Hepatol Int

Chronic hepatitis B

Hepatology

Treatment of chronic hepatitis B virus infection—Dutch national guidelines

Neth J Med

Lamivudine for patients with chronic hepatitis B and advanced liver disease

N Engl J Med

Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B

Hepatology

Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection

Hepatology

Interferon-alpha-2a. A review of its pharmacological properties and therapeutic use in the management of viral hepatitis

Drugs

Long-term remission of chronic hepatitis B after alpha-interferon therapy

Ann Intern Med

A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group

N Engl J Med

7
Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues