Purpose of Review: Concurrent HIV and hepatitis B virus (HBV) affect an estimated 4– 5 million people worldwide and remain a major driver of liver-related morbidity and mortality, even among individuals receiving tenofovir-containing antiretroviral therapy (ART). Both viruses establish long-lived reservoirs that are not eliminated by current antiviral therapies. This review summarizes current mechanistic and clinical frameworks for understanding concurrent HIV and HBV, highlights the interplay between their viral reservoirs, and discusses the implications of these interactions for cure strategies. Recent Findings: The liver functions as a multicellular reservoir. HBV persists within hepatocytes as nuclear covalently closed circular DNA (cccDNA) and integrated viral sequences. HIV persists as integrated provirus in tissue-resident CD4⁺ T cells and liver macrophages, with evidence supporting viral transfer or cell-to-cell spread involving stellate cells and hepatocytes. Concurrent HIV and HBV accelerate fibrosis and immune dysfunction through shared pathogenic pathways, including epigenetic silencing, cytokine- and checkpoint-mediated T-cell exhaustion, metabolic stress, and inflammation driven by the gut–liver axis. HBV-associated liver injury promotes recruitment of HIV target cells, while HIV-associated immune dysregulation impairs HBV control. Despite these interlinked biological mechanisms, individuals living with HIV and HBV are frequently excluded from clinical trials, slowing therapeutic progress and exacerbating health inequities. Summary: Concurrent HIV and HBV represent a synergistic disease model that demands integrated therapeutic approaches and inclusive research frameworks. Priority needs include robust tissue-based reservoir measurements, validated biomarkers that distinguish latent from transcriptionally active viral states, combination strategies incorporating antiviral, antifibrotic, and immunomodulatory agents, and community-engaged clinical trial designs that are inclusive of individuals living with HIV and HBV and safe in the context of HBV. Advancing these areas will be essential to achieving durable remission—and ultimately functional cure—for both viruses. Plain Language Summary: HIV and hepatitis B virus (HBV) often occur together and affect millions of people worldwide. Both viruses can persist in the liver, forming “viral reservoirs” that current treatments cannot eliminate. These hidden viral reservoirs contribute to long-term liver damage, including scarring (fibrosis) and liver cancer. This review explains how HIV and HBV interact and reinforce each other’s persistence. We describe how different liver cells—including immune cells and hepatocytes—create an environment that allows both viruses to survive. We also highlight emerging scientific tools and treatment strategies designed to better target viral reservoirs. Importantly, people living with HIV and HBV are often excluded from research studies. Including these individuals in future clinical trials will be essential to develop fair and effective cures for both viruses. Keywords: HIV, hepatitis B virus, liver, viral reservoirs, persistence, cure strategies
Bobadilla et al. (Sun,) studied this question.