Cryptic HBV Replicative Activity Is Frequently Revealed in Anti-HBc-Positive/HBsAg-Negative Patients with HIV Infection by Highly Sensitive Molecular Assays, and Can Be Predicted by Integrating Classical and Novel Serological HBV Markers

• Published in: Microorganisms
• Main Authors: Romina Salpini, Vincenzo Malagnino, Lorenzo Piermatteo, Tiziana Mulas, Mohammad Alkhatib, Rossana Scutari, Elisabetta Teti, Carlotta Cerva, Katia Yu La Rosa, Marta Brugneti, Ada Bertoli, Benedetta Rossi, Vera Holzmayer, Jeffrey Gersch, Mary Kuhns, Gavin Cloherty, Francesca Ceccherini-Silberstein, Carlo-Federico Perno, Marco Iannetta, Massimo Andreoni, Loredana Sarmati, Valentina Svicher
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Subjects: HBV; HIV; anti-HBc titer; anti-HBs titer; serum HBV-DNA; serum HBV-RNA
• Online Access: https://www.mdpi.com/2076-2607/8/11/1819

The anti-HBc-positive/HBsAg-negative status is frequent in HIV-infection and correlates with poor survival. Here, by highly-sensitive assays, we evaluate cryptic HBV replication and factors correlated with its detection in 81 anti-HBc-positive/HBsAg-negative HIV-infected patients. Patients were treated for >12 months with HBV-active modern combined antiretroviral-therapy (cART) and had serum HBV-DNA < 20 IU/mL by commercial Real-Time PCR. Serum HBV-DNA was quantified by droplet digital PCR, serum HBV-RNA by an Abbott research assay, and anti-HBc titer (proposed to infer intrahepatic cccDNA) by Lumipulse/Fujirebio. Cryptic serum HBV-DNA was detected in 29.6% of patients (median (IQR): 4(1–15) IU/mL) and serum HBV-RNA in 3.7% of patients despite HBsAg-negativity and HBV-active cART. Notably, cryptic serum HBV-DNA correlated with an advanced CDC-stage (<i>p</i> = 0.01) and a lower anti-HBs titer (<i>p</i> = 0.05), while serum HBV-RNA correlated with lower nadir CD4+ cell-count (<i>p</i> = 0.01). By analyzing serological HBV-markers, the combination of anti-HBs < 50 mIU/mL (indicating lower immune response) plus anti-HBc > 15COI (reflecting higher HBV replicative activity) was predictive of cryptic serum HBV-DNA (OR: 4.7(1.1–21.7), <i>p</i> = 0.046, PPV = 62.5%, and NPV = 72%). In conclusion, cryptic HBV-replication (not detected by classical assays) characterizes a conspicuous set of anti-HBc-positive HIV-infected patients despite HBsAg-negativity and HBV-active combined antiretroviral therapy (cART). The integration of classical and novel markers may help identify patients with cryptic HBV-replication, thus optimizing the monitoring of anti-HBc-positive/HBsAg-negative HIV-infected patients.