Background: Aim of the current study was to explore the incidence of malignancies and major adverse cardiovascular events (MACEs) in people living with 4-class drug-resistant HIV (4DR-PLWH).

Methods: Cohort study on PLWH with documented resistance to NRTIs, NNRTIs, PIs, and INSTIs, from the PRESTIGIO Registry.
The primary outcome was to evaluate the incidence rates (IRs) of malignancies and MACEs occurred after 4DR evidence (baseline, BL). Malignancies included both AIDS- and non-AIDS-related cancers. MACEs included stroke, acute myocardial infarction, coronary or peripheral artery disease requiring revascularization, and acute congestive heart failure.
Follow-up accrued from BL until death/loss-to-follow-up/freezing date (28th February, 2023).
Descriptions by median (interquartile range, IQR) or frequency (%). Poisson regression modelled IRs and 95% confidence intervals (95%CIs). Kaplan-Meier curves estimated cumulative probabilities of the first incident: 1) cancer; and 2) MACE.

Results: Overall, 229 4DR-PLWH included: BL characteristics reported in Table 1.
During a median follow-up of 7.7 (4.8-10.3) years [1760 person-years-of-follow-up (PYFU)], 28 (12.2%) 4DR-PLWH developed ≥1 incident cancer (n=30, Figure 1): IR=1.7 (95%CI=1.1-2.3)/100 PYFU. Specifically, 24 (80%) malignancies were non-AIDS-related: 7 HPV-related anal neoplasms, 4 Hodgkin lymphomas, 4 skin cancers, 2 hepatocellular carcinomas, 2 laryngeal carcinomas, 1 breast cancer, 1 lung cancer, 1 urothelial carcinoma, 1 cholangiocarcinoma, 1 conjunctival squamous cell carcinoma. Only 6 (20%) tumors were AIDS-defining: 4 high-grade non-Hodgkin lymphomas, and 2 Kaposi’s sarcomas. Notably, 2 individuals developed 2 different incident malignancies: one person developed Hodgkin lymphoma followed by non-Hodgkin lymphoma, the other a skin cancer followed by an HPV-related anal neoplasm. Furthermore, an individual who developed Kaposi’s sarcoma, had a prevalent HPV-related anal cancer at baseline.
Twenty-two (9.6%) 4DR-PLWH developed ≥1 MACE (n=31, Figure 1): IR=1.8 (95%CI=1.1-2.4)/100 PYFU. In particular, 15 myocardial infarctions, 8 acute congestive heart failures, 4 coronary diseases requiring revascularization, 3 strokes, and 1 peripheral artery disease requiring revascularization occurred. Remarkably, 5 individuals developed ≥2 incident MACEs: 2 events occurred in 2 individuals, 3 events in 2, 4 events in 1.
Cumulative probabilities of the first incident cancer and the first incident MACE reported in Figure 2.
Among 4DR-PLWH who experienced ≥1 incident malignancy or ≥1 incident MACE, 11 died: 8 after ≥1 tumor, 2 after ≥1 MACE, and 1 after both 1 malignancy and 1 MACE (Figure 1).

Conclusions: Due to high incidence of malignancies and MACEs in people living with multidrug-resistant HIV, screening and prevention strategies are strongly recommended in this fragile population.