Measurement of serum HBsAg in HIV/HBV coinfected patients predicts HBsAg clearance during long term exposure to tenofovir Zulema Plaza 1, Antonio Aguilera 2, Alvaro Mena 3, Luz Martín-Carbonero 1, Eugenia Vispo 1, Santiago Tomé 2, José Pedreira 3, Carmen Rodríguez 4, Vicente Soriano 1 & Eva Poveda 1 1 Hospital Carlos III, Madrid, Spain; 2 Hospital Conxo-CHUS, Santiago de Compostela, Spain; 3 Hospital Universitario de A Coruña, A Coruña, Spain; 4 Centro Sanitario Sandoval, Madrid, Spain
Background The use of potent nucleos(t)ide analogues (i.e. tenofovir) as part of antiretroviral combinations against HIV and HBV has favoured the control of HBV replication for long periods of time in most HIV/HBV coinfected patients. In this context, achievement of HBsAg seroconversion is the closest outcome to clinical cure in chronic HBV infection.
Role for HBsAg monitoring The HBsAg levels decline (> 0.5 log IU/mL) might predict sustained virological response in HBV monoinfected patients after interferon based therapy. Brunetto MR et al. Hepatology 2009;49:1141 50 Moucari R et al. Antivir Ther 2007;12:73 82 Sonneveld MJ et al. Hepatology 2010;52:1251 7 Marcellin P et al. Hepatology Int 2010;4:151 Lau G et al. J Hepatol 2009;50:S333 A rapid decline in HBsAg levels during nucleos(t)ide analogues therapy (Ldt or TDF) might identify HBV monoinfected and HBV/HIV coinfected patients with a higher chance for HBsAg seroconversion. Wursthorn K et al. Hepatology 2010;52:1611 1620 Heathcote EJ et al. Gastroenterology 2011;140:132 143
Objective To examine the rate of HBsAg seroconversion and the role of periodic HBsAg quantitative monitoring in a large cohort of HIV/HBV coinfected patients treated with tenofovir (TDF). Patients & Methods HBsAg+ patients followed at 3 clinics in Spain were identified. Demographic, coinfections (HCV, HDV), antiviral therapy and laboratory parameters (HIV RNA, HBV DNA, HBeAg, HBsAg, HBV genotype) were retrospectively recorded. Serum HBsAg levels were quantified using the Abbott ARCHITECT assay which depicts a dynamic range from 0.05 250 IU/ml. Samples were diluted 1:500 if necessary.
RESULTS
From a cohort of 147 HIV/HBV coinfected patients, 138 (94%) received TDF based therapy HIV/HBV Variables coinfected n=138 Male gender; n (%) [IQR] 120 (87) Median age; years [IQR] 45 [40 49] Positive baseline serum HBeAg; n (%) 64 (46.6) Median serum HBV DNA in viremic patients; log IU/mL [IQR] 6.4 [4.8 8] Undetectable serum HBV DNA; n (%) 41 (30) Hepatitis Delta virus antibody; n (%) 32 (23.2) Hepatitis C virus antibody; n (%) 29 (21) Previous HBV therapy; n (%) Lamivudine Entecavir Interferon 66 (48) 2 (1) 6 (4)
HBsAg clearance occurs in 6.5% of HIV/HBV coinfected patients after long term TDF exposure Variables HBsAg clearance (n=9) Median age; years [IQR] 47[41 51] Gender; Male/Female 9/0 Country Spain / Other 7/1 Risk factor IDU / Homosexual 4/4 Genotype A / D / F 3/2/1 Median of months on prior NA therapy [IQR] 27.5 [4.5 60.5] HCV RNA coinfection; n (%) 5 (55) HDV RNA coinfection ;n (%) 2 (22) CD4 cell count; cell/mm 3 [IQR] 587 [251 764] HBeAg negative; n (%) 8 (89) HIV RNA undetectable; n (%) 6 (62.5) Median ALT; IU/ml [IQR] 36 [24 48] Median baseline HBV DNA ;log IU/ml [IQR] 2.3 [1.9 5.6] Median baseline HBsAg ;log IU/ml [IQR] 1.4 [0.3 2.1] Median follow up on TDF therapy: 5[2.4 7.2] years
At TDF initiation, median HBsAg levels were lower in those patients who experienced HBsAg clearance. 0.001 p =0.001
A more pronounced HBsAg decline was observed in patients with HBsAg clearance than in those with persistent HBsAg. HBsAg clearance n=9 HBsAg persistence n=42 p HBsAg decline overtime [IQR], log IU/ml. 2.6 [IQR: 2 3.8] 1.8 [IQR:0.9 2.4] 0.027 Baseline CD4 cellcount [IQR], cell/mm 3 587 [251 764] 358 [228 504] 0.1
Rate of HBsAg levels based on HBV genotypes and HBeAg status. p=0.03 p=ns p=0.02
Low baseline HBsAg levels and a HBsAg decline > 0.5 log IU/ml/year are independent predictors of HBsAg clearance after 5 years under TDF therapy Endpoint Co variable p OR 95% CI Baseline CD4>500 cell/mm 3 0.13 HBsAg clearance Baseline HBsAg levels log IU/ml 0.016 0.3 0.1 0.8 HBsAg decline >0.5 log IU/ml/year 0.021 230 2.1 23609 *HBeAg status, months on TDF therapy and overall exposure to NA was taken into account in the multivariate analysis
Conclusions The rate of HBsAg clearance was 6.5% in a large cohort of HIV/HBV coinfected patients after long term TDF exposure. IntheunivariateanalysisbaselineHBsAglevels,HBeAg status and HBsAg decline are associated with HBsAg clearance. Baseline HBsAg levels and a HBsAg decline > 0.5 log IU/ml/year were identified as independent predictors of HBsAg clearance after 5 years under TDF therapy.
Acknowledgments Hospital Carlos III Dr. Vicente Soriano Dra. Eugenia Vispo Dra. Luz Martín Carbonero Dra. Eva Poveda Centro Sanitario Sandoval Dra. Carmen Rodríguez Hospital Conxo CHUS, Santiago de Compostela Dr. Antonio Aguilera Dr. Santiago Tomé Hospital Universitario de A Coruña Dr. Álvaro de Mena Dr. José Pedreira