Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B

Micco, L.; Peppa, Dimitra; Loggi, Elisabetta; Schurich, Anna; Jefferson, Lucy; Cursaro, Carmela; Panno, Arianna Martello; Bernardi, Mauro; Berthou, Christian; Bihl, Florian; Andreone, Pietro; Maini, Mala K.

doi:10.1016/j.jhep.2012.09.029

Cited by 204 publications

(225 citation statements)

References 27 publications

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“…However, experimental studies have shown that only a small percentage of patients on INF-α therapy experience loss of surface-antigen, e-antigen loss and reduction in virus replication [45]. Moreover, interferon-α is responsible for only partial reversal of T cell inactivation in chronic hepatitis B infections [37] and is not induced naturally during acute hepatitis B infections [46].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, interferon-α is responsible for only partial reversal of T cell inactivation in chronic hepatitis B infections [37] and is not induced naturally during acute hepatitis B infections [46]. However, interferon-α therapy induces cccDNA degradation in cell culture [47] and enhances the innate immune response mediated by natural killer (NK) cells in e-antigen negative patients [45]. Our optimal control study predicts that enhanced cccDNA degradation, which can be incorporated in our model as an effect on the term ρ, has limited effect on the timing of HBV DNA removal (not shown).…”

Section: Discussionmentioning

confidence: 99%

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Optimal Control of Drug Therapy in a Hepatitis B Model

et al. 2016

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Combination antiviral drug therapy improves the survival rates of patients chronically infected with hepatitis B virus by controlling viral replication and enhancing immune responses. Some of these drugs have side effects that make them unsuitable for long-term administration. To address the trade-off between the positive and negative effects of the combination therapy, we investigated an optimal control problem for a delay differential equation model of immune responses to hepatitis virus B infection. Our optimal control problem investigates the interplay between virological and immunomodulatory effects of therapy, the control of viremia and the administration of the minimal dosage over a short period of time. Our numerical results show that the high drug levels that induce immune modulation rather than suppression of virological factors are essential for the clearance of hepatitis B virus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Optimal Control of Drug Therapy in a Hepatitis B Model

et al. 2016

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“…Accumulating evidence suggested that long-term NUC therapy enhances and complements the immunomodulatory effects of IFN in CHB patients, while IFN may inhibit formation of HBV protein and deplete the intrahepatic covalently closed circular DNA (cccDNA) pool (7,8). Therefore, the optimization of combining IFN (Peg-IFN-␣2a) and NUCs, such as ETV, may lead to the complete eradication of HBV.…”

Section: Discussionmentioning

confidence: 99%

“…However, some recent studies have demonstrated that longterm NUC monotherapy can restore HBV-specific T-cell responsiveness (7), which may address a limitation of Peg-IFN-␣ therapy (8). Thimme and Dandri (9) argue that the addition of Peg-IFN-␣ to ongoing NUC therapy after restoration of HBVspecific T-cell responsiveness may be an effective strategy.…”

mentioning

confidence: 99%

Sequential Combination Therapy with Pegylated Interferon Leads to Loss of Hepatitis B Surface Antigen and Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Chronic Hepatitis B Patients Receiving Long-Term Entecavir Treatment

Chen

et al. 2015

Antimicrob Agents Chemother

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e Nucleos(t)ide analogues rarely result in a durable off-treatment response in chronic hepatitis B infection, whereas pegylated interferon (Peg-IFN) induces a long-lasting response only in a subset of patients. We assessed the effect of sequential combination therapy with Peg-IFN-␣2a and entecavir in hepatitis B e antigen (HBeAg)-positive patients with prior long-term entecavir therapy and investigated the predictors of response to treatment. HBeAg-positive individuals who did not achieve HBeAg seroconversion during previous long-term entecavir therapy, receiving Peg-IFN-␣2a added to ongoing entecavir therapy (sequential combination [S-C] therapy; n ‫؍‬ 81) for 48 weeks or remaining on entecavir monotherapy (n ‫؍‬ 116), were retrospectively included. A matched pair was created at a 1:1 ratio from each treatment group. The primary endpoint was HBeAg seroconversion at week 48. Subgroup analysis of response prediction was conducted for 81 patients with S-C therapy. More patients in the S-C therapy group achieved HBeAg seroconversion than those in the entecavir group (44% versus 6%; P < 0.0001). An HBeAg level of <200 signal-to-cutoff ratio (S/CO) at baseline was a strong predictor for higher HBeAg seroconversion than that achieved when HBeAg was >200 S/CO (64.2% versus 17.9%; P < 0.0001). Hepatitis B surface antigen (HBsAg) levels at baseline and the decrease in HBsAg levels predicted HBsAg loss in the S-C therapy group. The combination of baseline HBeAg of <200 S/CO and HBsAg of <1,000 IU/ml and an HBsAg decline at week 12 of >0.5 log 10 IU/ml provided the highest rate of HBeAg seroconversion (92.31%) and HBsAg loss (83.3%) at week 48. Patients receiving sequential combination therapy have a higher rate of HBeAg seroconversion and are more likely to experience HBsAg clearance than do those continuing entecavir monotherapy. Sequential combination therapy can be guided by baseline HBsAg/HBeAg levels and on-treatment HBsAg dynamics. Hepatitis B virus (HBV) infection is endemic in Asia, the Pacific islands, Africa, Southern Europe, and Latin America, and chronic hepatitis B (CHB) is a global health threat. There are approximately 350 million chronic HBV surface antigen (HBsAg) carriers worldwide (1). Patients with CHB have an increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), which results in about 1 million deaths per year (2). Antiviral treatment is effective in halting progression of CHB in many patients. Two classes of antiviral agents are available: nucleos(t)ide analogues (NUCs), such as entecavir (ETV), which inhibit the viral polymerase and interfere with viral replication, and interferon alpha (IFN-␣), including conventional and pegylated forms, which has antiviral and immunomodulatory effects (3). NUCs are effective in most patients but must be continued indefinitely in the patients that do not achieve hepatitis B e antigen (HBeAg) seroconversion. In contrast, a finite course of pegylated IFN-␣ (Peg-IFN-␣) can induce a long-lasting therapeutic response, but on...

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“…IFN-a is an immune modulator that induces, in a nonspecific manner, the expression of interferon-stimulated genes (ISGs) encoding intracellular or secreted proteins with direct or indirect antiviral properties in both infected and noninfected cells, and promotes the differentiation/activation of immune cells (Samuel 2001;Sadler and Williams 2008). In the HBV setting, the IFN-a antiviral activity results from a complex mode of action including the activation of natural killer (NK)/ NKT cells, inhibition of viral genome transcription, destabilization of viral nucleocapsid, but also, as recently suggested, degradation of covalently closed circular DNA (cccDNA) via the activation of APOBEC3A in infected cells (Micco et al 2013;Thimme and Dandri 2013;Lucifora et al 2014).…”

Section: Background-basis Of Anti-hepatitis B Virus (Hbv) Therapymentioning

confidence: 99%