The D:A:D study is a prospective study formed by the collaboration of 11 cohorts in Europe, Australia, and the United States. Information on all AIDS events, including all aids-defining cancers, has been provided prospectively on an annual basis since the start of the study in 1999.

This study assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma).

All participating cohorts have been collecting information prospectively on NADC from 2008 or earlier; information was also collected retrospectively on events occurring from January 1, 2004, to January 31, 2008. Detailed information on each NADC is collected on a specific case report form. D:A:D participants were followed until the earliest of a first incident cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Poisson regression models were used to assess associations between the incidence of cancer and cumulative exposure to cART, defined as any regimen including a PI or NNRTI. Initial analyses considered associations with cumulative exposure to any cART, with subsequent models then considering associations with exposure to the PI and NNRTI classes separately. Models were adjusted for gender, participating cohort, mode of HIV acquisition, ethnic group, any previous cancer (all as fixed covariates), age (as a continuous, time-updated covariate), calendar year, body mass index, previous AIDS diagnosis, HBV status, HCV status, and smoking status (all as time-updated covariates). Sensitivity analyses considered whether conclusions were modified after adjusting for either the baseline or nadir (time updated) CD4 count.

A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1,832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72-0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1,114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)].

In conclusion, the cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.