HBsAg clearance in chronic hepatitis B patients with add-on pegylated interferon alfa-2a to ongoing tenofovir treatment: A randomized controlled study

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Abstract

Background/Aims:

The ideal end point of treatment for chronic hepatitis B virus (HBV) infection is sustained off-therapy hepatitis B surface antigen (HBsAg) loss with or even without seroconversion to anti-HBs. We investigated the role of adding PEGylated interferon (PEG IFN) to ongoing tenofovir treatment in chronic HBV patients for achieving HBsAg clearance.

Patients and Methods:

In this randomized controlled trial, chronic HBV patients who have been receiving tenofovir for >6 months with HBV viral load <2000 IU/ml were randomized into two groups. One group (add-on therapy) was given subcutaneous PEG IFN 180 mcg weekly for 12 months in addition to tenofovir. Patients in the other group received only tenofovir 300 mg orally on a daily basis. Patients in both groups were followed up for a total of two years, and patients in both groups were given tenofovir 300 mg daily indefinitely until they developed HBsAg clearance.

Results:

Twenty-three patients were allocated to the PEG IFN and tenofovir (add-on therapy) group, and another 25 patients were recruited to the tenofovir monotherapy group. Before randomization, patients had received tenofovir for 1135 mean days (range203 to 1542 days). One patient (4.3%) in add-on therapy lost HBsAg and seroconverted. Within two years, mean HBsAg decreased significantly with add-on therapy (from 4753 IU/ml to 2402; P = 0.03); and it decreased from 5957 IU/ml to 4198; P = 0.09 in tenofovir monotherapy group. More patients in the add-on group developed serious side effects, with treatment discontinuation, and dose reductions ( P = 0.3).

Conclusion:

PEG IFN and tenofovir add-on therapy was successful in achieving HBsAg clearance and seroconversion in 4.3% of the patients. Add-on therapy patients had a significant decrease in HBsAg levels in two years; and no significant decrease in HBsAg levels with the tenofovir monotherapy. With no significant HBsAg clearance, the utility of this combination regimen is questionable.

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Most cited references 22

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Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.

George K. K. Lau, Teerha Piratvisuth, Kang Luo … (2005)

Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

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Hepatitis B virus immunopathogenesis.

F V Chisari, C. Ferrari (1995)

Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.

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Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.

Patrick Marcellin, George K. K. Lau, Ferruccio Bonino … (2004)

Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications. We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks. After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy. Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates. Copyright 2004 Massachusetts Medical Society

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Author and article information

Journal

Journal ID (nlm-ta): Saudi J Gastroenterol

Journal ID (iso-abbrev): Saudi J Gastroenterol

Journal ID (publisher-id): SJG

Title: Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 1319-3767

ISSN (Electronic): 1998-4049

Publication date (Print): May-Jun 2017

Volume: 23

Issue: 3

Pages: 190-198

Affiliations

[1]Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

[1 ]Department of Microbiology Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

[2 ]Department of Pharmaceutical Care Services, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Author notes

Address for correspondence: Dr. Musthafa C. Peedikayil, Department of Medicine, MBC 46, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. E-mail: musthafacpdr@ 123456gmail.com

Article

Publisher ID: SJG-23-190

DOI: 10.4103/sjg.SJG_541_16

PMC ID: 5470379

PubMed ID: 28611343

SO-VID: 4d84de59-a180-4826-89c6-2a039d94c50b

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

HBsAg clearance in chronic hepatitis B patients with add-on pegylated interferon alfa-2a to ongoing tenofovir treatment: A randomized controlled study

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Abstract

Background/Aims:

Patients and Methods:

Results:

Conclusion:

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Karger: Gastroenterology

Most cited references 22

Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.

Hepatitis B virus immunopathogenesis.

Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.

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