The optimal management strategy for children with immune‐tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune‐tolerant phase of HBV infection. Children with immune‐tolerant features of chronic hepatitis B (CHB) received entecavir once‐daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa‐2a (180 µg/1.73m2 subcutaneously) once‐weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4‐17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty‐five children completed the entire 48‐week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti–hepatitis B surface antigen antibody (anti‐HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty‐seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune‐tolerant phase of HBV infection, and treatment was associated with frequent AEs.

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.

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Background and Aims Treatment of immune‐tolerant (IT) children and adults with combined peginterferon alfa‐2a and entecavir results in a decline in serum HBeAg and HBsAg concentrations but rarely results in loss of HBeAg or sustained off‐treatment response. Factors associated with declines in these viral antigens during treatment remain unexplored. Approach and Results We investigated the pattern of virologic and biochemical response in 86 participants (59 children, 27 adults) by serial quantitative measurement of HBsAg (qHBsAg), quantitative HBeAg (qHBeAg), HBV RNA, interferon‐inducible protein (IP‐10), IL‐18, and alanine aminotransferase (ALT). Each individual had previously been treated with 8 weeks of entecavir followed by 40 weeks of combined peginteferon and entecavir. We defined the interrelationships between these parameters and virologic response measured as nadir declines from baseline for HBeAg and HBsAg. The patterns of HBsAg and HBeAg decline were similar in pediatric and adult participants. Higher levels of IP‐10 were observed during treatment in participants with greater ALT elevations and greater reductions of qHBsAg and qHBeAg. Individuals with peak ALT values exceeding three times the upper limit of normal were significantly more likely to have >1 log10 decline in both viral antigens. HBV DNA became undetectable in 21 of 86 (24%) and HBV RNA in 4 of 77 (5%) during therapy, but both markers remained negative only in those who became HBsAg negative, all of whom also had ALT elevations. Conclusions Induction of IP‐10 during peginterferon treatment in adults and children in the IT phase of chronic HBV infection is associated with ALT elevations and decline in viral antigens, suggesting a degree of interferon‐inducible viral control.

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Summary Background Patient‐reported outcomes (PROs) such as health‐related quality of life (HRQoL) and symptoms associated with chronic hepatitis B viral (HBV) infection have not been well‐described in North American cohorts. Aims To evaluate several PROs and associations with HBV disease activity markers. Methods Cross‐sectional analysis including 876 adults who completed PRO measures during the Hepatitis B Research Network Adult Cohort Study. Participants on HBV treatment were excluded. Outcomes included: HRQoL using the SF‐36 mental component summary and physical component summary scores; symptom burden using a 10‐item Total Symptom Checklist and fatigue using an instrument from the Patient‐Reported Outcomes Measurement Information System®. Covariates included laboratory markers of disease severity, virological status, comorbidities and medications. Results Median age was 42 (range: 19‐79), 51% were female, 73% Asian, 19% HBeAg (+), 2% had AST‐platelet ratio index (APRI) ≥1.5 and 74% without comorbidities. Mean mental component summary T‐score = 52, physical component summary T‐score = 54 and PROMIS Fatigue T‐score = 47. On a scale from 0 (none) to 40 (extreme), the mean Symptom Checklist score = 3 and 25% reported no symptoms. The most frequent symptoms were fatigue (60%), irritability (32%) and itching (32%). Most symptoms were ‘a little bit’ bothersome. In multivariable regressions, APRI ≥1.50 and more comorbidities were associated with worse patient‐reported outcomes; virological markers were not. Adding the Total Symptom Checklist score to original regression models increased explanation of variation in the mental component summary score from 4% to 44% and the Physical Component Summary Score from 17% to 34%. Conclusions Untreated North American HBV patients with mild liver disease report favourable health‐related quality of life and minimal symptoms. HBV does not impact health‐related quality of life unless advanced liver disease or comorbidities are present. High symptom burden explains substantial variation in health‐related quality of life. (CT.gov identifier: NCT01263587).

CM is a social determinant of midlife HRQoL in women. The relationship between CM and MCS was partially explained by psychosocial mediators. It is important to increase awareness among health professionals that a woman's midlife well-being may be influenced by early-life adversity.

Introduction and objectives: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. Materials and methods: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. Results: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing ( p = 0.02) or diagnosis of HBV ( p = 0.02). Conclusions: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5–15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.