Decay of ccc-DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients

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• 作者：Anders Boyd¹ ; Karine Lacombe² ; ³ ; Fabien Lavocat⁴ ; Sarah Maylin⁵ ; ⁶ ; Patrick Miailhes⁷ ; Caroline Lascoux-Combe⁸ ; Constance Delaugerre⁵ ; ⁶ ; ⁹ ; Pierre-Marie Girard² ; ³ ; Fabien Zoulim⁴ ; ¹⁰ ; ^{fabien.zoulim@inserm.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HBV ; hepatitis B virus ; cccDNA ; covalently-closed circular DNA ; IH-DNA ; intrahepatic DNA ; HIV ; human immunodeficiency virus ; HBeAg ; hepatitis B &ldquo ; e&rdquo ; antigen ; IQR ; interquartile range ; TDF ; tenofovir ; HCC ; hepatocellular carcinoma ; NA ; nucleoside/nucleotide analogue ; ETV ; entecavir ; HBsAg ; hepatitis B surface antigen ; ART ; antiretroviral therapy ; qHBsAg ; quantification of hepatitis B surface antigen ; LAM ; lamivudine ; ADV ; adefovir ; CTL ; cytotoxic T lymphocytes ; AIDS ; acquired immunodef
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：65
• 期：4
• 页码：683-691
• 全文大小：813 K

文摘

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.