Non-AIDS defining malignancies in the combination ART era: immunological and socio-behavioral risk factors [version 1; peer review: 2 approved with reservations]

Background: Since the advent of combination antiretroviral therapy (cART), non-AIDS defining malignancies (NADM) have become increasingly important. We examined risk factors for NADM, including immunological, virological and socio-behavioral characteristics. Methods: We linked the Swiss HIV Cohort Study (SHCS) with cancer registries to identify incident cancers between 1996 and 2012. We analyzed four common NADM: anal, lung, prostate, and liver cancer. We calculated standardized incidence ratios (SIRs) and assessed the effect of time-updated CD4 and CD8 count, CD4/CD8 ratio, and HIV viral load (copies/ml) in Cox regression models. We lagged time-dependent variables for 12, 24, and 36 months and captured cumulative exposures using simple moving averages (SMA). In multivariable models, we also considered HIV transmission group, smoking, and chronic hepatitis B or C infection as potential predictors of NADM incidence. Results. Between 1996 and 2012, 563 HIV-infected individuals developed NADM, including 70 anal, 49 lung, 44 prostate, and 36 liver cancers. Compared with the general population, the SHCS exhibited higher rates of anal (SIR 76.1, 95% Confidence interval (CI) 60.2-96.2), lung (SIR 1.98, 1.50-2.62), and liver cancer (SIR 7.28, 5.25-10.1) but similar rates of prostate cancer (SIR 1.03, 0.76-1.38). Anal cancer was associated with low CD4 cell count, high CD8 cell count, men who have sex with men, and smoking. For lung cancer, the CD8 cell count was the only significant predictor identified among the immunological and virological factors. CD4 cell count, and chronic hepatitis B and C infection were predictive of liver cancer incidence. We found no evidence of any of the immunological factors being associated with prostate cancer. Conclusions: The importance of immunodeficiency (indexed by CD4 count) and immune senescence (indexed by CD8 count) differs across NADM. Immunodeficiency was an important risk factor for anal and liver cancer whereas immune senescence was associated with lung cancer and anal cancer.