OBJECTIVE:Hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) loss are important clinical outcomes for patients with chronic hepatitis B (CHB) treated withantiviral therapy. To date, there have been few studies that have evaluated viral sequence markers predicting serological response to nucleos(t)ide analogue (NA) treatment. DESIGN: We used next-generation sequencing (NGS) and quantitative HBV serology (HBeAg and HBsAg) to identify viral sequence markers associated with serological response to long-term tenofovir disoproxil fumarate therapy among HBeAg-positive patients. In the GS-US-174-0103 study, approximately half the patients seroconverted to anti-HBe by week 192 and 11% of patients exhibited HBsAg loss, the closest outcome to functional cure. The frequency of HBV variants that have previously been associated with HBV clinical outcomes was evaluated. HBV viral diversity in baseline sequences generated by NGS was calculated using Shannon entropy. RESULTS: NGS analysis of HBV sequences from 157 patients infected with genotypes A to D showed the frequency of variants in the basal core promoter (BCP) and precore (PC) regions varied by genotype and that these mutations were associated with the absence of HBsAg loss. This was the case even when mutations were present at frequencies below the threshold of detection by population sequencing. Increased viral diversity across the HBV genome as determined by NGS was also associated with reduced likelihood of HBsAg loss. CONCLUSION: Patients with detectable BCP and/or PC variants and higher viral diversity have a lower probability of HBsAg loss during long-term NA therapy. Strategies to achieve functional cure of HBV infection through combination therapy should consider using NGS to stratify patients according to BCP/PC sequence. Consideration should also be given to earlier initiation of therapy prior to the emergence of BCP/PC variants. TRIAL REGISTRATION NUMBER: NCT00116805; Post result. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
RCT Entities:
OBJECTIVE:Hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) loss are important clinical outcomes for patients with chronic hepatitis B (CHB) treated with antiviral therapy. To date, there have been few studies that have evaluated viral sequence markers predicting serological response to nucleos(t)ide analogue (NA) treatment. DESIGN: We used next-generation sequencing (NGS) and quantitative HBV serology (HBeAg and HBsAg) to identify viral sequence markers associated with serological response to long-term tenofovir disoproxil fumarate therapy among HBeAg-positive patients. In the GS-US-174-0103 study, approximately half the patients seroconverted to anti-HBe by week 192 and 11% of patients exhibited HBsAg loss, the closest outcome to functional cure. The frequency of HBV variants that have previously been associated with HBV clinical outcomes was evaluated. HBV viral diversity in baseline sequences generated by NGS was calculated using Shannon entropy. RESULTS: NGS analysis of HBV sequences from 157 patients infected with genotypes A to D showed the frequency of variants in the basal core promoter (BCP) and precore (PC) regions varied by genotype and that these mutations were associated with the absence of HBsAg loss. This was the case even when mutations were present at frequencies below the threshold of detection by population sequencing. Increased viral diversity across the HBV genome as determined by NGS was also associated with reduced likelihood of HBsAg loss. CONCLUSION:Patients with detectable BCP and/or PC variants and higher viral diversity have a lower probability of HBsAg loss during long-term NA therapy. Strategies to achieve functional cure of HBV infection through combination therapy should consider using NGS to stratify patients according to BCP/PC sequence. Consideration should also be given to earlier initiation of therapy prior to the emergence of BCP/PC variants. TRIAL REGISTRATION NUMBER: NCT00116805; Post result. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Timothy M Block; Stephen Locarnini; Brian J McMahon; Barbara Rehermann; Marion G Peters Journal: Clin Infect Dis Date: 2017-05-01 Impact factor: 9.079
Authors: Anna Kramvis; Kyong-Mi Chang; Maura Dandri; Patrizia Farci; Dieter Glebe; Jianming Hu; Harry L A Janssen; Daryl T Y Lau; Capucine Penicaud; Teresa Pollicino; Barbara Testoni; Florian Van Bömmel; Ourania Andrisani; Maria Beumont-Mauviel; Timothy M Block; Henry L Y Chan; Gavin A Cloherty; William E Delaney; Anna Maria Geretti; Adam Gehring; Kathy Jackson; Oliver Lenz; Mala K Maini; Veronica Miller; Ulrike Protzer; Jenny C Yang; Man-Fung Yuen; Fabien Zoulim; Peter A Revill Journal: Nat Rev Gastroenterol Hepatol Date: 2022-07-20 Impact factor: 73.082
Authors: Peter A Revill; Thomas Tu; Hans J Netter; Lilly K W Yuen; Stephen A Locarnini; Margaret Littlejohn Journal: Nat Rev Gastroenterol Hepatol Date: 2020-05-28 Impact factor: 46.802
Authors: Marion G Peters; Shyam Kottilil; Norah Terrault; Dominic Amara; Jennifer Husson; Shirish Huprikar; Sander Florman; Mark S Sulkowski; Christine M Durand; Anne F Luetkemeyer; Rodney Rogers; Joshua Grab; Brandy Haydel; Emily Blumberg; Lorna Dove; Jean Emond; Kim Olthoff; Coleman Smith; Thomas Fishbein; Henry Masur; Peter G Stock Journal: Am J Transplant Date: 2020-12-23 Impact factor: 8.086