title: Decay of ccc-DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients.
abstract: 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.
  
  
  
  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.
  
  
  
  At biopsy, 35 (58.3%) patients were hepatitis B "e" antigen (HBeAg)-positive and 33 (55.0%) had detectable plasma HBV-DNA (median=4.58log10IU/ml, IQR=2.95-7.43). Overall, median cccDNA was -0.95log10copies/cell (IQR=-1.70, -0.17) and total IH-DNA was 0.27log10copies/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/mm(3), and longer cumulative TDF-duration, but not lamivudine- or adefovir-duration. In post-hoc analysis using reconstructed TDF-duration (median 29.6months, IQR=15.0-36.1, n=31), average half-life of cccDNA was estimated at 9.2months (HBeAg-positive=8.6, HBeAg-negative=26.2) and total IH DNA at 5.8months (HBeAg-positive=1.3, HBeAg-negative=13.6). Intrahepatic viral loads remained detectable for all patients, even with prolonged TDF-exposure.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F75012 Paris, France.
authors.forename: Anders
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), F75012 Paris, France; Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Lacombe
authors.affiliation: Cancer Research Center of Lyon, INSERM, Unité 1052, CNRS, UMR 5286, Université de Lyon, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lavocat
authors.affiliation: Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France; Université Paris-Diderot, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Maylin
authors.affiliation: Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Miailhes
authors.affiliation: Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Louis, AP-HP, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lascoux-Combe
authors.affiliation: Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France; Université Paris-Diderot, Paris, France; INSERM U941, Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), F75012 Paris, France; Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.affiliation: Cancer Research Center of Lyon, INSERM, Unité 1052, CNRS, UMR 5286, Université de Lyon, Lyon, France; Hepatology Department, Hospices Civils de Lyon, Lyon, France. Electronic address: fabien.zoulim@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000998:Antiviral Agents; D060085:Coinfection; D004270:DNA, Circular; D004279:DNA, Viral; D015658:HIV Infections; D006509:Hepatitis B; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus; D006801:Humans; D000068698:Tenofovir
chemical_list: D000998:Antiviral Agents; D004270:DNA, Circular; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D000068698:Tenofovir
keywords: Exponential decay; Hepatitis B virus; Intrahepatic HBV-DNA; Nucleoside/nucleotide analogue; cccDNA