Persistent viremia in human immunodeficiency virus/hepatitis B coinfected patients undergoing long-term tenofovir: Virological and clinical implications

Authors

  • Anders Boyd,

    Corresponding author
    1. INSERM UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
    • Address reprint requests to: Anders Boyd, M.P.H., Ph.D., Services des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. E-mail: boyd@u707.jussieu.fr; fax: +33 1 49 28 21 49.

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  • Joël Gozlan,

    1. Laboratoire de Virologie, Hôpital Saint-Antoine, Paris, France
    2. UPMC UMRS CR7; INSERM U1135 CIMI, Paris, France
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  • Sarah Maylin,

    1. Laboratoire de Virologie, Hôpital Saint-Louis, Paris, France
    2. INSERM U941, Paris, France
    3. Université Paris-Diderot, Paris, France
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  • Constance Delaugerre,

    1. Laboratoire de Virologie, Hôpital Saint-Louis, Paris, France
    2. INSERM U941, Paris, France
    3. Université Paris-Diderot, Paris, France
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  • Gilles Peytavin,

    1. Hôpital Bichat-Claude Bernard, Laboratoire de Pharmacologie, AP-HP and INSERM UMR 1137 IAME, Paris, France
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  • Pierre-Marie Girard,

    1. INSERM UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
    2. Sorbonne Universités, Paris, France
    3. Service de maladies infectieuses, Hôpital Saint-Antoine, Paris, France
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  • Fabien Zoulim,

    1. INSERM U1052, Lyon, France
    2. Hepatology Unit, Hospices Civils de Lyon, Lyon, France
    3. Université de Lyon, Lyon, France
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  • Karine Lacombe

    1. INSERM UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
    2. Sorbonne Universités, Paris, France
    3. Service de maladies infectieuses, Hôpital Saint-Antoine, Paris, France
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  • Potential conflict of interest: Nothing to report.

  • This study has been funded, in part, by Sidaction (AO 19) and received additional grants from ANRS (Agence Nationale de Recherche sur le Sida et les Hépatites). Gilead Sciences, Inc., provided an unrestricted grant for the French HIV-HBV cohort. Roche Diagnostics gave additional funding for antigen quantification. Both Gilead Sciences, Inc., and Roche Diagnostics were not involved in any part of the data collection, analysis, and manuscript writing. A.B. was awarded a postdoctoral fellowship from the ANRS.

Abstract

Tenofovir (TDF) is considered the ideal treatment for patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, certain coinfected patients exhibit incomplete viral suppression, with persistent, and sometimes transient, bouts of HBV replication. The reasons for this, including clinical effect, are unclear. A total of 111 HIV-HBV-infected patients undergoing TDF-containing antiretroviral therapy were prospectively followed. Serum HBV-DNA viral load, hepatitis surface (HBsAg) and e antigen (HBeAg) status were obtained at baseline and every 6-12 months. Amino acid (aa) changes on the polymerase gene were assessed using direct sequencing after nested polymerase chain reaction in patients with persistent viremia (PV). After a median of 74.7 months (interquartile range: 33.4-94.7), virological response (VR; <60 IU/mL) occurred in 96 of 111 (86.5%) patients. Of these, 86 of 96 (89.6%) remained completely undetectable during follow-up (stabilized VR). The remaining 10 of 96 (10.4%) patients had a transient blip of detectable HBV-DNA (transient PV), during which time 9 of 9 (100%) with available samples had detectable plasma TDF. Low-level PV (LL-PV; 61-2,000 IU/mL) was observed in 11 of 111 (9.9%) patients, the majority of which had detectable plasma TDF (8 of 9; 88.9%). High-level PV (>2,000 IU/mL) was rare (4 of 111; 3.6%) and was associated with nonadherence. At TDF initiation, patients with stabilized VR had significantly higher nadir CD4+ count, compared to those with transient PV (P = 0.006) or LL-PV (P = 0.04). No consistent aa changes, other than those associated with lamivudine resistance, were observed in patients with persistent viremia. Importantly, HBeAg loss, HBeAg seroconversion, and HBsAg loss only occurred in patients with stabilized VR. Two patients with stabilized VR developed hepatocellular carcinoma and 2 with LL PV died, 1 of a liver-related cause. Conclusion: Suboptimal HBV control during TDF treatment has a negative effect on serological outcomes, but not necessarily clinical events. Immunoregulation may provide more insight into this phenomenon. (Hepatology 2014;60:497–507)

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