Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B

Marcellin, Patrick; Ahn, Sang Hoon; Ma, Xiao; Căruntu, Florin Alexandru; Tak, Won Young; Elkashab, Magdy; Chuang, Wan‐Long; Lim, Seng Gee; Tabak, Fehmı; Mehta, Rajiv; Petersen, J.; Foster, Graham R.; Lou, Lillian; Martins, Eduardo B.; Dinh, Phillip; Lin, Lanjia; Corsa, Amoreena C.; Charuworn, Prista; Subramanian, G. Mani; Reiser, Hans; Reesink, H.W.; Fung, Scott; Strasser, Simone I.; Trinh, Huy N.; Buti, María; Gaeta, Giovanni Battista; Hui, Aric Josun; Papatheodoridis, George V.; Flisiak, Robert; Chan, H.L.Y.

doi:10.1053/j.gastro.2015.09.043

Cited by 293 publications

(309 citation statements)

References 32 publications

(19 reference statements)

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“…1,130 In a recent randomised controlled trial, the 72-week HBsAg loss rates were superior in the PegIFNa and TDF treated patients compared to those observed in patients receiving PegIFNa alone or TDF alone (9% vs. 3% vs. 0%) but the overall rates were low and mainly confined to genotype A patients. 62 pretreatment with NA improves the rates of sustained response to PegIFNa. 130,132,133 The multicentre ARES study demonstrated that a 24-week course of PegIFNa, given to a small group of HBeAg-positive patients who were on ETV therapy for only 24 weeks, can improve the kinetics of HBeAg, HBV DNA and HBsAg, compared to those on ETV monotherapy, but a PegIFNa monotherapy arm was missing.…”

Section: Na Plus Pegifna Recommendationsmentioning

confidence: 97%

“…Theoretically, a combined NA and PegIFNa approach may provide advantages by combining the potent antiviral effect of NA plus the immune modulation of IFNa. 1,56,62,63 The evidence for superiority of such a combined approach, however, is lacking, and there are still many unresolved issues with respect to patient selection, timing, as well as the duration of the combination strategy, which may be addressed in future studies.…”

Section: 5657mentioning

confidence: 99%

“…The sustainability of HBsAg loss and seroconversion after PegIFNa is good although HBsAg seroreversions have been described. 62,106 In HBeAg-negative CHB patients, the 48-week PegIFNa registrational trial showed sustained biochemical and virological response rates of 60% and 44% at 6 months and of 31% and 28% at 3 years after the end of therapy 1,107 (Table 4 HBsAg loss rarely occurred during PegIFNa therapy in HBeAgnegative CHB patients, but the rate of HBsAg loss progressively increased after PegIFNa discontinuation, from 3% at month 6 to 9% at year 3 to 12% at year 5 in the registrational trial 1 (Table 4).…”

Section: Efficacy Recommendationsmentioning

confidence: 99%

See 2 more Smart Citations

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

Lampertico¹,

Agarwal²,

Berg³

et al. 2017

Journal of Hepatology

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4,032

3,081

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Section: Na Plus Pegifna Recommendationsmentioning

confidence: 97%

Section: 5657mentioning

confidence: 99%

Section: Efficacy Recommendationsmentioning

confidence: 99%

See 1 more Smart Citation

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

Lampertico¹,

Agarwal²,

Berg³

et al. 2017

Journal of Hepatology

Self Cite

4,032

3,081

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“…PEG-IFN monotherapy has been reported to result in hepatitis B e antigen (HBeAg) seroconversion in 29 to 32% of patients and in hepatitis B surface antigen (HBsAg) loss in 3 to 7% of patients at 24 weeks after completion of treatment (11,14). Combination therapy with both an NA and PEG-IFN-␣-2a has been shown to result in greater viral decline and HBeAg loss than NA therapy alone (15)(16)(17)(18) and resulted in reduced HBV cccDNA in chronic hepatitis B patients (19,20). Therefore, we hypothesized that combination therapy with high doses of NA and PEG-IFN could eliminate HBV infection in an immunodeficient animal model.…”

Section: H Epatitis B Virus (Hbv) Infection Is the Most Common Chronimentioning

confidence: 99%

Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

Uchida

Imamura

Hayes

et al. 2017

Antimicrob Agents Chemother

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Nucleot(s)ide analogues and peginterferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long-term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for 6 weeks. High-dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA at 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B corerelated antigen (HBcrAg) continued to decrease and eventually became negative at 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G-to-A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high-dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.

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“…Increasingly, clinical studies evaluating a finite duration of NA therapy are being undertaken [9]. With new therapeutic targets identified [10], future HBV therapy is likely to be more individualized and utilize sequential or combinations of drugs that target specific host and viral pathways to achieve functional cure. With these future therapies, reports from high-quality ''real-world'' cohorts will continue to inform practice by providing safety and effectiveness data across diverse treatment settings and in a broader array of patients.…”

mentioning

confidence: 99%

Real-World Experiences with Tenofovir Disoproxil Fumarate: Is this the “B-Ticket”?

Terrault

2016

Dig Dis Sci

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The preferred options for treatment of chronic hepatitis B viral (HBV) infection in countries without resource constraints are peginterferon, entecavir, or tenofovir disoproxil fumarate (TDF) [1,2]. For most clinicians, peginterferon is infrequently considered due to the greater complexity of monitoring, higher frequency of adverse effects and patient preference, which narrows the treatment options to TDF or entecavir. In the registration trials of treatment-naïve patients with chronic hepatitis B, both TDF and entecavir demonstrated high rates of on-treatment HBV DNA suppression and low rates of viral resistance coupled with excellent safety [3,4]. Given that TDF and entecavir have been approved therapies for HBV for more than a decade, data derived from ''real-world'' cohort studies have helped fill knowledge gaps regarding the use of these drugs in clinical practice. In the case of TDF, the issues of particular interest include: (1) the efficacy of TDF across a wider spectrum of patients including those less adherent than patients in clinical trials, and (2) the risks associated with longer-term use of TDF, especially the frequency of viral resistance and the risk of renal and bone toxicity.Patients participating in clinical trials are a select group-typically healthier than many patients in the clinic, with fewer comorbidities and higher rates of adherence. The registration trials for TDF required a estimated glomerular filtration rate (eGFR) [70 ml/min, absence of anemia, neutropenia, and liver decompensation or presence of unstable comorbidities [3]. In practice, patient complexity can be greater, comorbidities not always optimized, and adherence less assured. Understanding how antivirals perform under these less than ideal circumstances is important. The ideal ''real-world'' study would prospectively enroll consecutive patients and account for all patients at study end, provide intent-to-treat as well as perprotocol analyses, and include details of treatment failures, including reasons for treatment discontinuation. The ''realworld'' cohorts included in this issue of Digestive Diseases and Sciences-GEMINIS from Germany [5] and VIREAL from France [6]-partially meet these high standards. Regardless, some important practical messages can be gleaned from their analyses.The VIREAL and GEMINIS cohorts enrolled [800 patients from diverse practice settings who were newly initiated on TDF therapy [5,6]. Treatment-naïve and experienced subjects were included, with a substantial proportion of the treatment-experienced patients transitioning from another nucleos(t)ide analog therapy to TDF and having low or undetectable HBV DNA levels at the time of TDF initiation. Hypertension, diabetes, renal disease, cardiovascular diseases, and other comorbidities were present in *40 % of patients [5] with up to 28 % having eGFR \90 ml/min [6]. Although the intent of the study was to follow patients for 3 years, both cohorts suffered from patient attrition, leading to incomplete reporting of virologic and safety data. The primary...

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Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B

Abstract: A significantly greater proportion of patients receiving TDF plus peginterferon for 48 weeks had HBsAg loss than those receiving TDF or peginterferon alone. ClinicalTrials.gov ID NCT01277601.

Cited by 293 publications

References 32 publications

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

Real-World Experiences with Tenofovir Disoproxil Fumarate: Is this the “B-Ticket”?

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