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

Abstract

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...

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

“…135,136 Two additional Asian studies assessed whether a 48-week course of add-on PegIFNa was superior to long-term NA therapy in HBeAg-positive patients. 137,138 While the HBsAg decline was superior in the combination group, the HBsAg loss rates did not increase significantly. In HBeAg-negative CHB patients under NA treatment, two multicentre European studies have assessed the safety and efficacy of a 48-week add-on course of PegIFNa.…”

Effects of pegylated interferon‐α based therapies on functional cure and the risk of hepatocellular carcinoma development in patients with chronic hepatitis B

“…A multicenter, retrospective study conducted in China investigated patients diagnosed with HBeAg‐positive CHB who had not achieved HBeAg seroconversion during prior ETV treatment for ≥2 years and then received either peg‐IFN‐α‐2a added to ongoing ETV therapy for 48 weeks (combination therapy group) or remained on entecavir (ETV monotherapy group). The HBeAg seroconversion rate at week 48 was significantly higher in the combination therapy group than in the ETV monotherapy group (44% vs 6%, respectively; P < 0.001).…”

Optimal Control of Drug Therapy in a Hepatitis B Model

“…Combined antiviral therapy improves the survival rates of patients chronically infected with hepatitis B virus [42]. While the first goal of therapy is to reduce HBV replication, the ultimate goal is the removal of hepatitis B surface and e-antigens and of covalently-closed circular DNA (cccDNA).…”