Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis <scp>B</scp>

Wong, Grace Lai–Hung; Wong, Vincent Wai‐Sun; Chan, Henry Lik‐Yuen

doi:10.1111/jvh.12341

Cited by 35 publications

(32 citation statements)

References 76 publications

(86 reference statements)

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“…The available treatment options for CHB include interferon, pegylated interferon (Peg-IFN), and five oral nucleotide analogues (NAs)2. The anti-HBe seroconversion rates of current therapies are approximately 30% with Peg-IFN and 20% with NAs34.…”

mentioning

confidence: 99%

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Shen

Liu

et al. 2016

Sci Rep

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A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy.

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confidence: 99%

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Shen

Liu

et al. 2016

Sci Rep

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“…Once the second medication is added, we have the option of continuing both PEG IFN and NAs or discontinuing one of them. [611]…”

Section: Discussionmentioning

confidence: 99%

“…However, a high HBV DNA load reduces the T-cell response to HBV-related antigens. [67] HBV DNA markedly gets suppressed with NAs treatment, and as a result, the body restores CD4 and CD8 cellular immune response against HBV. The addition of IFN at this stage enhances the immunomodulatory action and clearance of the cccDNA.…”

Section: Introductionmentioning

confidence: 99%

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

Ashgar

Peedikayil

Quaiz

et al. 2017

Saudi J Gastroenterol

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“…A few controlled clinical studies addressing NAs or NA plus interferon combination therapies against HBV have been undertaken, but there is little evidence of the clinical benefit of this approach (14,35). Therefore, establishing whether combination therapy with newer agents provides increased benefit over monotherapy remains an urgent task.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interactions between Hepatitis B Virus RNase H Antagonists and Other Inhibitors

Lomonosova

Zlotnick

Tavis

2017

Antimicrob Agents Chemother

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Combination therapies are standard for management of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections; however, no such therapies are established for human hepatitis B virus (HBV). Recently, we identified several promising inhibitors of HBV RNase H (here simply RNase H) activity that have significant activity against viral replication in vitro. Here, we investigated the in vitro antiviral efficacy of combinations of two RNase H inhibitors with the current anti-HBV drug nucleoside analog lamivudine, with HAP12, an experimental core protein allosteric modulator, and with each other. Anti-HBV activities of the compounds were tested in a HepG2-derived cell line by monitoring intracellular core particle DNA levels, and cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. The antiviral efficiencies of the drug combinations were evaluated using the median-effect equation derived from the mass-action law principle and combination index theorem of Chou and Talalay. We found that combinations of two RNase H inhibitors from different chemical classes were synergistic with lamivudine against HBV DNA synthesis. Significant synergism was also observed for the combination of the two RNase H inhibitors. Combinations of RNase H inhibitors with HAP12 had additive antiviral effects. Enhanced cytotoxicity was not observed in the combination experiments. Because of these synergistic and additive effects, the antiviral activity of combinations of RNase H inhibitors with drugs that act by two different mechanisms and with each other can be achieved by administering the compounds in combination at doses below the respective single drug doses.

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Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B

Cited by 35 publications

References 76 publications

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

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

Synergistic Interactions between Hepatitis B Virus RNase H Antagonists and Other Inhibitors

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