Persistence of CXCR4-tropic virus in people living with four-class drug-resistant HIV and its clinical impact in the modern antiretroviral era

Background CXCR4-tropic HIV seems to be associated with more clinical events than CCR5-tropic virus. Objectives This study aims to describe the effect of the persistence of CXCR4-tropic virus on the occurrence of clinical events in people with four-class drug-resistant HIV. Methods This is a retrospective study on people with four-class drug-resistant HIV from the PRESTIGIO Registry, with at least two HIV-tropism determinations during follow-up. Follow-up accrued from the date of the first four-class drug resistance evidence (baseline) until death, loss to follow-up or freezing date (31 December 2023). Univariable Poisson regression was used to estimate and compare incidence rates of clinical events. Predictors of clinical events were assessed by multivariable Poisson regression. Results A total of 144 people with four-class drug-resistant HIV [47 (33%) with persistent CXCR4-tropism, 39 (27%) with persistent CCR5-tropism and 58 (40%) with a tropism switch during follow-up] were included with a median follow-up of 7.80 years (IQR = 5.80-10.6). Overall, 117 (81.3%) 4DR-PLWH experienced at least one clinical event during follow-up [incidence rate = 32.5 (95% CI = 29.3-35.9)]. The persistence of CXCR4-tropic virus was associated with an increased risk of HIV-related events among people living with four-class drug-resistant HIV, even in modern ART era. After adjusting for age, sex at birth and CD4+/CD8+ at baseline, standardized viremia copy-years [adjusted-incidence rate ratio = 1.66 (95% CI = 1.24-2.26), P < 0.001] and persistent CXCR4-tropism [adjusted-incidence rate ratio: 2.01 (95% CI = 1.04-3.91), P = 0.037] were associated with the occurrence of HIV-related events. Conclusions Our findings confirm CXCR4-tropism as a marker of HIV progression also in the four-class drug-resistant population, suggesting the need of further prioritization of viro-immunological control and studies of pathogenic mechanisms in presence of CXCR4-tropic multidrug-resistant viral strains.