TY - JOUR
T1 - Decay of ccc-DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients
AU - Boyd, Anders
AU - Lacombe, Karine
AU - Lavocat, Fabien
AU - Maylin, Sarah
AU - Miailhes, Patrick
AU - Lascoux-Combe, Caroline
AU - Delaugerre, Constance
AU - Girard, Pierre-Marie
AU - Zoulim, Fabien
N1 - Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Background & Aims In the presence of highly-potent antivirals, persistence of hepatitis B virus (HBV) is most well-characterized by covalently-closed circular DNA (cccDNA) and total intrahepatic DNA (IH-DNA). We sought to determine how antiviral therapy could affect their levels during human immunodeficiency virus (HIV)-HBV co-infection. Methods Sixty co-infected patients from a well-defined cohort with ⩾1 liver biopsy were studied. HBV cccDNA and total IH-DNA were extracted from biopsies and quantified by real-time PCR. Factors associated with intrahepatic viral load were determined using mixed-effect linear regression and half-life viral kinetics during reconstructed follow-up using non-linear exponential decay models. Results At biopsy, 35 (58.3%) patients were hepatitis B “e” antigen (HBeAg)-positive and 33 (55.0%) had detectable plasma HBV-DNA (median = 4.58 log10 IU/ml, IQR = 2.95–7.43). Overall, median cccDNA was −0.95 log10 copies/cell (IQR = −1.70, −0.17) and total IH-DNA was 0.27 log10 copies/cell (IQR = −0.39, 2.00). In multivariable analysis, significantly lower levels of cccDNA and total IH-DNA were observed in patients with HBeAg-negative serology, nadir CD4+ cell counts >250/mm3, and longer cumulative TDF-duration, but not lamivudine- or adefovir-duration. In post-hoc analysis using reconstructed TDF-duration (median 29.6 months, IQR = 15.0–36.1, n = 31), average half-life of cccDNA was estimated at 9.2 months (HBeAg-positive = 8.6, HBeAg-negative = 26.2) and total IH DNA at 5.8 months (HBeAg-positive = 1.3, HBeAg-negative = 13.6). Intrahepatic viral loads remained detectable for all patients, even with prolonged TDF-exposure. Conclusions In co-infection, TDF-use is associated with lower levels of HBV replication intermediates and cccDNA. Slow decay of intrahepatic viral loads underscores that TDF is unable to completely block intracellular viral DNA synthesis, which possibly accounts for continuous replenishment of the cccDNA pool. Lay summary Chronic hepatitis B virus (HBV) is a persistent infection, while the only real way of knowing the extent of this persistence is through measuring levels of virus in the liver. In this study, we examine levels of HBV in the liver among patients with both HBV and human immunodeficiency virus, or HIV, infection. It would appear that the currently available medication, namely “tenofovir”, works well to decrease virus levels in the liver, but it remains at low levels despite long periods of treatment.
AB - Background & Aims In the presence of highly-potent antivirals, persistence of hepatitis B virus (HBV) is most well-characterized by covalently-closed circular DNA (cccDNA) and total intrahepatic DNA (IH-DNA). We sought to determine how antiviral therapy could affect their levels during human immunodeficiency virus (HIV)-HBV co-infection. Methods Sixty co-infected patients from a well-defined cohort with ⩾1 liver biopsy were studied. HBV cccDNA and total IH-DNA were extracted from biopsies and quantified by real-time PCR. Factors associated with intrahepatic viral load were determined using mixed-effect linear regression and half-life viral kinetics during reconstructed follow-up using non-linear exponential decay models. Results At biopsy, 35 (58.3%) patients were hepatitis B “e” antigen (HBeAg)-positive and 33 (55.0%) had detectable plasma HBV-DNA (median = 4.58 log10 IU/ml, IQR = 2.95–7.43). Overall, median cccDNA was −0.95 log10 copies/cell (IQR = −1.70, −0.17) and total IH-DNA was 0.27 log10 copies/cell (IQR = −0.39, 2.00). In multivariable analysis, significantly lower levels of cccDNA and total IH-DNA were observed in patients with HBeAg-negative serology, nadir CD4+ cell counts >250/mm3, and longer cumulative TDF-duration, but not lamivudine- or adefovir-duration. In post-hoc analysis using reconstructed TDF-duration (median 29.6 months, IQR = 15.0–36.1, n = 31), average half-life of cccDNA was estimated at 9.2 months (HBeAg-positive = 8.6, HBeAg-negative = 26.2) and total IH DNA at 5.8 months (HBeAg-positive = 1.3, HBeAg-negative = 13.6). Intrahepatic viral loads remained detectable for all patients, even with prolonged TDF-exposure. Conclusions In co-infection, TDF-use is associated with lower levels of HBV replication intermediates and cccDNA. Slow decay of intrahepatic viral loads underscores that TDF is unable to completely block intracellular viral DNA synthesis, which possibly accounts for continuous replenishment of the cccDNA pool. Lay summary Chronic hepatitis B virus (HBV) is a persistent infection, while the only real way of knowing the extent of this persistence is through measuring levels of virus in the liver. In this study, we examine levels of HBV in the liver among patients with both HBV and human immunodeficiency virus, or HIV, infection. It would appear that the currently available medication, namely “tenofovir”, works well to decrease virus levels in the liver, but it remains at low levels despite long periods of treatment.
KW - Antiviral Agents
KW - Coinfection
KW - DNA, Circular
KW - DNA, Viral
KW - HIV Infections
KW - Hepatitis B
KW - Hepatitis B e Antigens
KW - Hepatitis B virus
KW - Humans
KW - Tenofovir
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84991628961&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/27210429
U2 - https://doi.org/10.1016/j.jhep.2016.05.014
DO - https://doi.org/10.1016/j.jhep.2016.05.014
M3 - Article
C2 - 27210429
SN - 0168-8278
VL - 65
SP - 683
EP - 691
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -