We thank Peppa et al for their thoughtful response to our review and for contributing important emerging data on immune phenotypes in HIV/HBV co-infection.Their observations add valuable mechanistic insight, particularly by highlighting distinctions in immune remodeling between treated and untreated states of HIV/HBV co-infection in individuals receiving long-term HBV-active antiretroviral therapy.Such data are important for refining our understanding of host-virus interactions in the modern treatment era.We agree that the immunologic landscape of treated HIV/HBV co-infection is more complex than a uniformly detrimental model would imply.The reported findings of enhanced adaptive NK-cell activity and preserved HBV-specific CD8 + T-cell responses in well-characterized cohorts of individuals with HIV/HBV co-infection receiving long-term suppressive therapy are significant 1,2 and may help explain clinical observations such as higher rates of HBsAg clearance reported in people with co-infection following initiation of HBV-active ART. 3,4These findings appropriately emphasize that effective treatment can partially reshape immune dysfunction associated with chronic dual infection.However, extrapolation of these observations to imply a protective or advantageous state would be premature.Rather, they highlight context-dependent immune adaptation under conditions of sustained viral suppression, which does not negate the broader evidence of increased clinical risk.A substantial body of evidence continues to demonstrate that untreated or incompletely treated HIV/HBV co-infection is associated with greater immune dysregulation, accelerated liver disease, and worse long-term outcomes than either infection alone. 566]7 Importantly, our use of the term "synergistic reinforcement" was intended to reflect the overall biological and clinical trajectory across disease states, rather than a uniform immunologic phenotype under all treatment conditions.As Peppa et al note, co-infection is not benign.Comparable examples have been described in other chronic viral infections.In patients with HBV and HCV coinfection, the introduction of direct acting antivirals for hepatitis C led to reports of HBV reactivation, including severe and occasionally fatal cases, following rapid HCV clearance. 8This phenomenon likely reflects the removal of suppressive antiviral pathways induced during chronic HCV infection.Similarly, cytomegalovirus can enhance specific immune modulatory responses while simultaneously driving chronic inflammation, immune senescence, and end-organ disease, particularly in older adults and immunocompromised individuals. 9,10These examples demonstrate that measurable immune effects during co-infection do not necessarily translate into reduced clinical risk.The same principle applies to HIV/HBV co-infection in the tenofovir era.Although HBV-active antiretroviral therapy has markedly improved prognosis, 11 it is premature to conclude that fibrosis progression, hepatic decompensation, or liver-related mortality have normalized.Several longitudinal studies continue to show progression to advanced fibrosis or persistent cirrhosis in a subset of treated individuals, and fibrosis regression appears less pronounced than that reported in Infection and Drug Resistance 2026:19 621913 1
Bobadilla et al. (Fri,) studied this question.