Antiviral Resistance and Persistence in HIV and HBV: Mechanisms and Challenges

Abstract

Antiviral resistance and viral persistence remain major obstacles to the long-term control and functional cure of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Although contemporary antiviral therapies can effectively suppress viral replication, they rarely eliminate the cellular and molecular reservoirs that sustain infection, while selective drug pressure can promote the emergence of resistant viral variants. In HIV infection, resistance is primarily associated with genetic mutations arising during incomplete viral suppression, inadequate adherence, pharmacokinetic variability, and prolonged exposure to antiretroviral drugs. The persistence of transcriptionally silent proviral DNA within long-lived CD4+ T cells further complicates eradication because these reservoirs can remain undetected during suppressive therapy and contribute to viral rebound following treatment interruption. In HBV infection, persistence is strongly linked to the formation and stability of covalently closed circular DNA (cccDNA) within hepatocyte nuclei, as well as the integration of viral DNA into the host genome. Nucleos(t)ide analogue therapy efficiently suppresses HBV replication but has limited effects on established cccDNA, creating a biological foundation for long-term viral persistence. Resistance in HBV can additionally arise through polymerase-associated mutations, particularly when antiviral suppression is incomplete. Recent research has therefore shifted toward strategies that simultaneously address viral replication, resistant variants, latent reservoirs, and host–virus interactions. Approaches under investigation include latency reversal and immune-based interventions for HIV, alongside capsid assembly modulators, entry inhibitors, RNA interference, therapeutic vaccines, and agents targeting cccDNA transcription or stability for HBV. Understanding the distinct yet interconnected mechanisms underlying antiviral resistance and persistence is essential for developing durable treatment strategies.