Risk of Cancer in People With Human Immunodeficiency Virus Experiencing Varying Degrees of Immune Recovery With Sustained Virological Suppression on Antiretroviral Treatment for More Than 2 Years: An International, Multicenter, Observational Cohort

Background: The impact of long-term virological suppression and CD4 count recovery on non-AIDS defining cancers (NADC) is unclear. We determined whether poor immune recovery was associated with incident cancer risk in people with HIV with virological suppression (VS). Methods: Participants from the D:A:D and RESPOND collaborations in Europe and Australia who achieved ≥2 years of VS on ART between Dec 1999 and Dec 2022 were included. Follow-up was from baseline (date of VS for two years) until the earliest of a first cancer event, virological failure, final follow-up, or administrative censoring date. Multivariable Poisson regression was used to assess associations between cancer incidence (overall, AIDS-defining cancer (ADC), NADC, infection-related, infection-unrelated) and time-updated CD4 count stratified by pre-ART nadir CD4 counts. Results: Overall, 48,343 people with VS were included (median [IQR] baseline age 43 years [37-50], CD4 count 540 cells/µL [380-730], nadir CD4 count 245 cells/µL [121-394], 74% male). There were 1,933 incident cancers, median 6.2 years [2.9-9.5] (incidence rate (IR): 6.43 [95%CI 6.15-6.73]/1000 person-years). Higher time-updated CD4 count was associated with a reduced risk of overall cancer (adjusted incidence rate ratio [aIRR] for time-updated CD4 350-499: 0.45 [95%CI 0.39-0.51]; 500-749: 0.30 [0.27-0.34], and ≥750: 0.26 [0.23-0.30] vs. <350 cells/µL, p<0.0001). There was a significant reduction in all cancers risk by higher time-updated CD4 count regardless of nadir CD4 count, with higher pre-ART nadir CD4 count exhibiting lower risk. Conclusions: Despite VS on ART for more than two years, people with poorer immune recovery experience a significantly higher incidence of cancer.