D:A:D and RESPOND collaborators combined longitudinal prospective data to assess whether poor immune recovery, despite virological suppression (VS) < 200 copies/mL, was independently predictive of cancer.  Incident cases were centrally validated and reviewed by an external oncologist, and were grouped as AIDS-defining (ADC), non-AIDS-defining (NADC), infection-related, infection-unrelated, smoking-related, and/or obesity-related.  Data from 48,343 participants achieving ≥ 2 years of VS were included: 74.4% were male, median age 43 years, median 7.4 years since HIV diagnosis, and median pre-ART CD4 nadir was 245 cells/µL.  Over 300,273 person years of follow-up, 3.9% participants developed cancer corresponding to an overall incidence rate (IR) of 6.43/1000 PYFU.  The most common were lung, anal and prostate, followed by non-Hodgkin’s lymphoma and breast cancer.  There were 258 ADC (0.5%) and 1675 NADC (3.5%) cases, corresponding to IRs of 0.86 and 5.58, respectively.  645 infection-related (IR 2.22) and 1,288 infection-unrelated (IR 4.29) cases were reported.  In multivariable analyses, higher time-updated CD4 was associated with a reduced risk of cancer development overall, with a linear trend by time-updated CD4 range: 350-499 cells/µL (aIRR 0.45), 500-749 cells/µL (aIRR 0.30), and ≥ 750 cells/µL (aIRR 0.26).  Results were consistent for both ADC and NADC and for infection-related and unrelated cancers.

Early and sustained antiretroviral therapy leading to durable virologic suppression remains the primary intervention for restoring immune function for people with HIV and reducing the development of certain cancers. However, D:A:D and RESPOND investigators observed that PWH with suboptimal immune recovery were still at increased risk of incident cancer across various categories despite ART-mediated virologic suppression. Authors highlight the ongoing importance of early screening/diagnosis with prompt ART initiation, as well as close attention to cancer screening especially for PWH with poor immune recovery.