In the START study, immediate antiretroviral therapy (ART) initiation reduced the overall risk of cancer by 64%. We hypothesized that the reduction in cancer risk was higher for infection-related vs infection-unrelated cancer and mainly determined by differences in CD4 counts and HIV RNA levels between the study arms.
Incident malignancies in START were categorized into any type, infection-related and infection-unrelated cancer. Infection-related cancer was defined as cancer driven by any infectious agent. Independent factors associated with each cancer category were assessed by multivariable Cox models. To investigate why immediate ART initiation reduced cancer risk we used sequential adjustment for baseline covariates, cancer risk factors and HIV-specific variables to fit Cox models with a study arm indicator.
There were 14 cancers among persons randomized to the immediate ART arm (6 infection-related and 8 infection-unrelated) and 39 cancers in the deferred arm (23 infection-related and 16 infection-unrelated) (Hazard Ratios [HR]; 95% CI; of immediate vs deferred ART initiation were 0.26; 0.11-0.64; for infection-related and 0.49; 0.21-1.15; for infection-unrelated cancer). In adjusted analyses with both treatment groups combined, older age (adjusted HR; 95% CI: 1.85; 1.44-2.39 per 10y), white race (2.80; 1.13-6.92 vs black) and HIV RNA (1.57; 1.08-2.28 per 1log higher) were linked to risk of any type cancer. Independent predictors of infection-related cancer were older age (1.42; 0.99-2.02 per 10y), higher BMI (1.08; 1.01-1.16 per Kg/m2), low income region (0.32, 0.14-0.74 for high vs low income) and HIV RNA (2.32; 1.35-3.98 per 1log higher). Older age was the only independent predictor of infection-unrelated cancer (2.58; 1.75-3.81 per 10y). Adjustment for latest HIV RNA level, but not for CD4 count or cancer risk factors, attenuated the effect of immediate ART on any type of cancer and infection-unrelated cancer (Figure). Adjustment for latest HIV RNA level had little impact on the protective effect of immediate ART on infection-related cancer.
Immediate ART initiation significantly reduces the risk of infection-related cancer. Though limited by small sample size, this benefit doesn’t appear to be solely attributable to HIV RNA suppression and may be also mediated by other mechanisms.