Forty-eight weeks of combination entecavir and peginterferon therapy rarely led to the loss of hepatitis B e antigen (HBeAg) with sustained suppression of hepatitis B DNA levels in children in the immune-tolerant phase of chronic hepatitis B infection, and was associated with frequent adverse events (AEs), according to a study published in Hepatology.

For children with immune-tolerant chronic hepatitis B, the optimal management strategy remains unknown. Though this clinical trial was originally intended to be a prospective, randomized, controlled study to assess the safety and efficacy of combination entecavir and peginterferon therapy in this population, the study was redesigned as single-arm treatment because of low enrollment. Some families expressed unwillingness to risk their child being randomized to observation instead of treatment, so participants initially randomly assigned to the control group were allowed to join the treatment arm if they still met the enrollment criteria.

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Ultimately, 60 children (75% girls, median age 10.9 years [range, 3.4-17.9]) with chronic hepatitis B with immunotolerant features received once-daily doses of entecavir 0.015 mg/kg (0.5 mg maximum) for 48 weeks, with once-weekly peginterferon alfa-2a (180 µg/1.73m² subcutaneously) added at the end of week 8 and continued through week 48. The primary end point was a lack of detectable HBeAg with hepatitis B virus DNA levels ≤1,000 IU/mL 48 weeks after therapy was stopped, and the primary safety end points were AEs and serious AEs (SAEs). The secondary end points measured at treatment’s end and 48 weeks later included loss of HBeAg and/or HBsAg, seroconversion of either HBsAg or HBeAg, normal alanine aminotransferase (ALT) levels (≤40 U/L for boys and ≤35 U/L for girls), hepatitis B virus DNA ≤1000 IU/mL and <20 IU/ mL, and normal growth parameters (height, weight, body mass index [BMI], and Tanner scores).

All 60 participants were positive for HBsAg and HBeAg and had high levels of hepatitis B virus DNA with normal or minimally elevated ALT levels. Forty-five of the initial 60 participants (75%) completed the full 48 weeks of entecavir therapy and the full 40 weeks of peginterferon therapy without early discontinuation or dose reduction. Five of the other 15 participants discontinued entecavir early (1 participant withdrew before starting peginterferon because of seizures), and 4 discontinued both treatments early (1 due to virologic breakthrough at week 33, 2 for thyroid conditions at weeks 36 and 44, and 1 due to investigator discretion at week 44). Ten participants had a dose reduction of peginterferon without discontinuation due to mild to moderate AEs.

Levels of ALT and aspartate aminotransferase were stable during entecavir monotherapy, but rose within 1 month of starting peginterferon. Peginterferon therapy was also associated with decreased white blood cell and platelet counts but there were no serious bacterial infections, and blood counts returned to baseline levels when peginterferon was stopped. HBsAg and HBeAg levels decreased in all children, usually starting at week 24 and continuing through week 48, with most decreases being mild to moderate. Levels of hepatitis B DNA decreased in all participants during treatment.

At the end of treatment, 45 children had HBV DNA ≤1,000 IU/mL (75%; 95% CI, 62.1-85.3), and levels were <20 IU/mL in 14 of these (23%; 95% CI, 13.4-36.0). At 48 weeks post-treatment discontinuation, only 2 children (3%; 95% CI, 0.4-11.5) had achieved the primary end point of lack of detectable HBeAg and hepatitis B virus DNA levels ≤1,000 IU/mL and had normal levels of ALT (11 and 14 U/L). These 2 participants, both Asian girls, ages 10.1 and 5.1 years, had also lost HBsAg by the end of treatment and developed both anti-HBe and anti-HBs and remained so at the end of post-treatment follow up. At week 96, hepatitis B DNA was undetectable (<10 IU/mL) in 1 of the girls and present but unquantifiable (<20 IU/mL) in the other.

The remaining participants had decreases in hepatitis B DNA levels during therapy, but these returned to near-baseline within 12 to 36 weeks post-treatment discontinuation, and none of the children became HBeAg or HBsAg negative at any time.

Thirty-seven participants reported 76 AEs, most of which were mild to moderate and were considered related to peginterferon, with a treatment-emergent AE rate of 70 per 100 person-years (95% CI, 56-87 per 100 person-years). The most common AEs were hepatic (elevated bilirubin or ALT; n=8; 11%), infectious (n=12; 16%), and hematologic (n=16; 21%). Of the 2 children who discontinued due to SAEs, only one was considered to be possibly related to peginterferon. The treatment-emergent rate of SAEs was 1 per 100 person-years (95% CI, 0-7 per 100 person-years).

Study investigators concluded, “in this open-label study of the combination of entecavir and peginterferon in 60 children with immune-tolerant chronic HBV infection, the overall response rate was low (3%) whereas adverse side effects were common, indicating that this approach is of limited and unsatisfactory efficacy. Nevertheless, the few responses that occurred were complete and convincing, which argues for increased efforts to identify better treatments for hepatitis B that might result in cure of this infection in a higher proportion of patients, including children with an immune-tolerant phenotype of disease.”

Disclosure: This clinical trial was supported by Bristol-Myers Squibb, Genentech, Inc., and Roche Molecular Systems, Inc. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Rosenthal P, Ling SC, Belle SH, et al; Hepatitis B Research Network (HBRN). Combination of entecavir/peginterferon alfa-2a in children with hepatitis B e antigen-positive immune tolerant chronic hepatitis B Virus infectionHepatology. 2019;69(6):2326-2337.