Entecavir and Peginterferon Alfa‐2a in Adults With Hepatitis B e Antigen–Positive Immune‐Tolerant Chronic Hepatitis B Virus Infection

Abstract

Monotherapy with interferon or nucleoside analog is generally not recommended during the immune‐tolerant (IT) phase of chronic hepatitis B virus (HBV) infection. Recognition that high HBV DNA levels are associated with hepatocellular carcinoma has increased interest in treating HBV in the IT phase. Small pediatric studies reported efficacy with combination nucleoside analog and interferon therapy. The aim of this study was to evaluate the safety and efficacy of the combination of entecavir and peginterferon in adults in the IT phase of chronic HBV infection. Hepatitis B e antigen (HBeAg)–positive adults with HBV DNA > 107 IU/mL and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal (ULN) (male: ≤ 45, female: ≤ 30 U/L) received entecavir 0.5 mg daily for 8 weeks followed by the addition of peginterferon alfa‐2a 180 µg/week to entecavir for an additional 40 weeks. The primary endpoint was HBeAg loss and HBV DNA ≤ 1,000 IU/mL 48 weeks after end of treatment (EOT). Among 28 participants from 11 sites, the median age was 37.2 (range: 22‐61) years, 54% were male, and 96% were Asian. Nearly all were infected with genotype C (64%) or B (32%). Median baseline HBV DNA was 8.2 log10 IU/mL, and ALT was 0.9 times the ULN. Although one (4%) participant cleared HBeAg, none met the primary endpoint of both HBeAg loss AND HBV DNA ≤ 1,000 IU/mL 48 weeks post‐EOT. ALT elevations > 5 times the ULN occurred in eight (29%) participants, and none were associated with icterus. Forty‐eight weeks posttreatment, HBV DNA rebounded to baseline levels in all participants, including the participant who lost HBeAg, and ALT values returned to near baseline levels in all but four participants. Conclusion: A lead‐in strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir therapy for 40 weeks had limited efficacy in adults in the IT phase of chronic HBV infection and cannot be recommended.

Histological responses of peginterferon alpha add‐on therapy in patients with chronic hepatitis B with advanced liver fibrosis after long‐term nucleos(t)ide analog treatment

“…The role of Peg‐IFNα in antiviral therapy in patients with CHB has been an interest of investigators for many years. The benefits of Peg‐IFNα monotherapy in combination with NAs, as well as addition to ongoing NAs, have been reported in different studies; however, these studies have primarily evaluated serological changes …”

Long-term nucleoside analogue therapy can lead effective HBV DNA inhibition in patients with chronic HBV infection in immune tolerate phase

“…Wu ZX [24] evaluated the efficacy of TDF and LDT combination therapy for chronic hepatitis B patients in IT phase and found that TDF and LDT combination therapy shows a rapid antiviral response in patients with CHB in IT phase. In another ETV and Peg IFN combination therapy study also shows potent antiviral response in patients with CHB in IT phase [17]. However, HBeAg seroconversion rate of patients in these studies was unsatisfactory.…”

“…Antiviral therapy with nucleos(t)ide analogues(NAs) can efficaciously inhibit viral replication, relieve liver inflammation, reverse liver fibrosis, reduce HCC incidence and thereby improve the clinical outcomes of patients with chronic HBV infection [10][11][12][13].Therefore, the existing national and international guidelines for the prevention and treatment of chronic hepatitis B (CHB) clearly recommend CHB patients during immune active (IA) phase (HBeAg positive or negative)to undergo antiviral treatment as soon as possible [14][15][16]. However, due to the presence of minimal liver inflammation, no obvious disease activity and poor antiviral efficacy of interferon (IFN) or NAs [17,18], the current mainstream treatment recommendations for CHB patients in immunetolerant (IT) phase are close follow-up until the entry into the IA period [14][15][16].…”

“…Given the strong correlation of high HBV DNA levels and the increased risk of HCC [7,19,20],and immunological and histological evidence for disease progression inpatients in IT phase [21,22], attention to antiviral strategies of IT patients had been increased [17,23,24]. The safety and efficacy of long-term treatment of NAs or IFN in patients in IT phases is still lacking.…”

Immune‐Tolerant Hepatitis B: Maybe a Misnomer but Still Hard to Treat

“…However, even if they are included, only 7% of treated patients reached the study endpoints. Feld and colleagues also report their experience in the current issue using a similar regimen in adults with IT chronic HBV . Only 1 (4%) of the 27 patients achieved HBeAg loss, with none experiencing durable HBV DNA suppression ≤1,000 IU off therapy.…”