Add-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs

doi:10.1016/j.jcv.2013.09.020

Journal of Clinical Virology

Volume 58, Issue 4, December 2013, Pages 713-717

https://doi.org/10.1016/j.jcv.2013.09.020 Get rights and content

Abstract

Background and objective

The aim of this study was to prospectively evaluate whether the addition of peg-IFN to a stable NA regimen leads to loss of HBsAg in HBeAg-negative patients with chronic hepatitis and HBV DNA fully suppressed by long-term NA treatment.

Study design

We analyzed HBsAg levels in 10 HBsAg-positive, HBeAg-negative patients who received peg-IFN alpha-2a in addition to a NA regimen. Treatment lasted a maximum of 96 weeks, according to changes in the HBsAg titer. Before peg-IFN therapy, HBV DNA levels had been below the limit of detection for at least three years.

Results

HBsAg levels declined in nine patients. Among these nine, four became HBsAg-negative after 48 weeks of peg-IFN treatment; these patients received peg-IFN for only 48 weeks. NAs were stopped in these four patients, and these levels remained stable for at least 18 months (loss of HBsAg; HBV-DNA negative). HBs seroconversion was observed in two patients. The remaining five patients received 96 weeks of peg-IFN therapy. One patient became HBsAg-negative at the end of peg-IFN therapy; another became HBsAg-negative six months later. Three patients did not become HBsAg-negative. NAs were stopped in the two patients who became HBsAg-negative with no relapse during 12 months of follow up.

Conclusions

In HBsAg-positive, HBeAg-negative patients with HBV DNA were fully suppressed by long-term NA treatment, the addition of peg-INF for a maximum of 96 weeks based on HBsAg-titer monitoring led to a loss of HBsAg and cessation of NA therapy in six out of ten patients, with no relapse for 12–18 months of follow up. HBs seroconversion was observed in two patients.

Section snippets

Background

HBeAg-negative chronic hepatitis B (CHB) is currently the predominant type of CHB in Europe and the Mediterranean basin [1], [2]. To date, two classes of drugs have been approved for the treatment of CHB: the immune-modulating drug pegylated interferon-alpha (peg-IFN) and inhibitors of viral replication, i.e., nucleotide analogs (NAs) [3], [4]. Oral NAs are a potent therapeutic option for CHB but require long-term, indefinite therapy [5], [6], [7]. Ideally, treatment of CHB should aim at

Objective

The aim of this study was to prospectively evaluate whether the addition of peg-IFN to a stable NA regimen leads to loss of HBsAg in HBeAg-negative patients with chronic hepatitis.

Patients

The inclusion criteria were HBsAg-positive, HBeAg-negative chronic hepatitis and long-term NA therapy with at least three years of fully suppressed viral load (limit of detection 20 IU/ml).

Ten consecutive patients were followed from September 2009 to March 2010 (median age 58 years old [min 41–max 76], all male). Peg-IFN alpha2a (Pegasys, Roche Pharma AG) was administered subcutaneously in a 180-μg dose once weekly for a maximum of 96 weeks. All patients had a viral load below the limit of

Results

As expected, minimal changes in HBsAg levels were observed in patients treated with NAs alone within the year before the start of peg-IFN therapy; the median decline was 5 IU/ml [95%CI 0–360] (Fig. 1, Fig. 2). During add-on peg-IFN therapy, HBsAg levels declined in nine out of ten patients; the median decline was 519 IU/ml [0–1997] (Fig. 1, Fig. 2). In one patient, HBsAg levels remained high, and peg-IFN therapy was stopped at week 24 (Fig. 2). This patient remained HBsAg-positive. Among the nine

Discussion

Even though the number of patients was limited, this study demonstrates for the first time that extending peg-IFN for up to 96 weeks in accordance with changes in HBsAg titers leds to HBsAg seronegativity in six out of 10 patients, with HBs seroconversion in two patients, regardless of the HBV genotype or IL28B status (Table 1). The maximum duration of peg-IFN treatment was established according to a recent study that showed a 96-week treatment course to be superior to a 48-week treatment

Funding

The authors declare that they did not have any financial support to conduct this study.

Competing interests

The authors declare that they do not have any conflict of interest.

Ethical approval

In accordance with French regulations, patients were informed that their sample could be used for research purposes and were free to refuse. Samples were used anonymously, with respect for medical confidentiality.

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Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial
2017, The Lancet Gastroenterology and Hepatology
Citation Excerpt :
Among patients with HBeAg-positive chronic hepatitis B, an early add-on strategy has been proven to be better than monotherapy in terms of sustained HBsAg reduction,23 although the primary endpoint (HBeAg loss with HBV DNA concentration <200 IU/mL) was not reached.24 Among patients with HBeAg-negative chronic hepatitis B, this add-on pegylated interferon strategy has already been shown in case reports25,26 and uncontrolled pilot studies,27,28 findings from which all show a deep decline in HBsAg titres with add-on treatment and a high proportion of HBsAg loss and HBs seroconversion. Therefore, we designed a randomised controlled trial to investigate the efficacy, safety, patient-reported outcomes, and predictors of response of addition of pegylated interferon for 48 weeks during analogue therapy in patients with HBeAg-negative chronic hepatitis B.
Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy.
In this randomised, controlled, open-label trial, we enrolled patients aged 18–75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (< or ≥2·25 log₁₀ IU/mL) to allocate patients (1:1) to receive a 48 week course of subcutaneous injections of 180 μg per week of pegylated interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392.
Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] to pegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analogues group from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI −2·6 to 12·5]; p=0·15). 85 (94%) of 90 patients started pegylated interferon, three (4%) of whom had a dose reduction and 17 (20%) had an early discontinuation of pegylated interferon (seven [41%] for serious adverse events). Grade 3 and 4 adverse events were more frequent in the pegylated interferon plus nucleos(t)ide analogues group (26 [29%] grade 3 adverse events; 19 [21%] grade 4 adverse events) than in the nucleos(t)ide analogues-alone group (three [3%] grade 3; six [6%] grade 4).
Addition of a 48 week course of pegylated interferon to nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B with undetectable HBV DNA for a least 1 year was poorly tolerated and did not result in a significant increase of HBsAg clearance.
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Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study)
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Short CommunicationAdd-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs

Abstract

Background and objective

Study design

Results

Conclusions

Section snippets

Background

Objective

Patients

Results

Discussion

Funding

Competing interests

Ethical approval

J Hepatol

J Clin Virol

J Hepatol

J Hepatol

World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants

J Viral Hepat

The natural history of chronic HBV infection and geographical differences

Antivir Ther

EASL Clinical Practice Guidelines: management of chronic hepatitis B

J Hepatol

EASL Clinical Practice Guidelines: management of chronic hepatitis B

J Hepatol

Predictors of relapse in chronic hepatitis B after discontinuation of anti-viral therapy

Aliment Pharmacol Ther

Poor durability of lamivudine effectiveness despite stringent cessation criteria: a prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients

J Gastroenterol Hepatol

Peginterferon plus adefovir versus either drug alone for hepatitis delta

N Engl J Med

Short Communication
Add-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs