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.
Bibliographical noteFunding Information:
Dr. Cloherty owns stock in and is employed by Abbott. Dr. Feld advises and received grants from Abbvie, Eiger, Enanta, Gilead, and Janssen. He advises Arbutus, Antios, GSK, and Vir. Dr. Lisker‐Melman is on the speakers’ bureau for Abbvie. Dr. Rosenthal consults for and received grants from Albireo, Arrowhead, Gilead, Mirum, Takeda/Vertex, and Travere. He consults for Ambys, Audentes, BioMarin, Dicerna, Encoded, and MedinCell. He received grants from Abbvie and Merck. Dr. Chung received grants from Gilead, Abbvie, Merck, BMS, Boehringer, Roche, and GSK. Dr. Schwarz consults for and received grants from Gilead. She advises Sarepta. She received grants from Albireo.
The Hepatitis B Research Network (HBRN) recently completed two clinical trials of peginterferon alfa‐2a (PegIFN) combined with entecavir during the IT phase of CHB, one in adults and a second in children. These studies were funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We previously reported that the treatment protocol had very limited efficacy in achieving the primary efficacy endpoints of HBeAg loss and HBV DNA level less than 1000 IU/ml at the end of a 48‐week posttreatment follow‐up period. However, a potentially important and somewhat unanticipated finding from this study was the demonstration of a decline in HBeAg and HBsAg concentration in many participants that appeared to be associated with alanine aminotransferase (ALT) elevations. However, it remains unknown to what extent these two factors are interrelated and why. Therefore, a secondary analysis of these two clinical trials was done to clarify the clinical significance of these associations and to determine factors associated with a greater decline in viral antigen levels. [ 10,11 ]
The HBRN was funded as a Cooperative Agreement between the NIDDK to the following investigators: Lewis R. Roberts, MB, ChB, PhD (U01‐DK082843), Anna Suk‐Fong Lok, MD (U01‐DK082863), Steven H. Belle, PhD, MScHyg (U01‐DK082864), Kyong‐Mi Chang, MD (U01‐DK082866), Michael W. Fried, MD (U01‐DK082867), Adrian M. Di Bisceglie, MD (U01‐DK082871), William M. Lee, MD (U01‐DK082872), Harry L. A. Janssen, MD, PhD (U01‐DK082874), Daryl T‐Y Lau, MD, MPH (U01‐DK082919), Richard K. Sterling, MD, MSc (U01‐DK082923), Steven‐Huy B. Han, MD (U01‐DK082927), Robert C. Carithers, MD (U01‐DK082943), Mandana Khalili, MD (U01‐DK082944), Kathleen B Schwarz (U01‐DK082916), an interagency agreement with NIDDK: Lilia M. Ganova‐Raeva, PhD (A‐DK‐3002‐001) and support from the intramural program, NIDDK, NIH: Marc G. Ghany, MD. Additional funding to support this study was provided to Kyong‐Mi Chang, MD, the Immunology Center, (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01‐RR00040), Richard K. Sterling, MD, MSc (UL1TR000058, NCATS (National Center for Advancing Translational Sciences, NIH), Norah A. Terrault, MD, MPH (CTSA Grant Number UL1TR000004), Michael W. Fried, MD (CTSA Grant Number UL1TR001111), Kathleen B. Schwarz, MD (CTSA Grant Number UL1 TR000423), and Anna Suk‐Fong Lok (CTSA Grant Number UL1RR024986, U54TR001959.) Entecavir was provided by Bristol Myers Squibb and peginterferon was provided by Genentech, Inc. through respective Clinical Trial Agreements with the NIDDK. Additional support was provided by Roche Molecular Systems, Inc. through a Cooperative Research and Development Agreement with the NIDDK
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