Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection

Abstract

Background. In the Strategic Timing of Antiretroviral Treatment (START) study, immediate combination antiretroviral therapy (cART) initiation reduced cancer risk by 64%. We hypothesized that risk reduction was higher for infection-related cancer and determined by differences in CD4 cell counts and human immunodeficiency virus (HIV) RNA between the study arms.Methods. Incident malignancies in START were categorized into infection-related and infection-unrelated cancer. We used Cox models to assess factors associated with both cancer categories. We used sequential adjustment for baseline covariates, cancer risk factors, and HIV-specific variables to investigate potential mediators of cancer risk reduction with immediate cART.Results. There were 14 cancers among persons randomized to immediate cART (6 infection-related and 8 infection-unrelated) and 39 cancers in the deferred arm (23 infection-related and 16 infection-unrelated); hazard ratios of immediate vs deferred cART initiation were 0.26 (95% confidence interval [CI], .11-.64) for infection-related and 0.49 (95% CI, .21-1.15) for infection-unrelated cancer. Independent predictors of infection-related cancer were older age, higher body mass index, low-to middle-income region, HIV RNA, and baseline CD8 cell count. Older age and baseline CD8 cell count were independent predictors of infection-unrelated cancer. Adjustment for latest HIV RNA level had little impact on the protective effect of immediate cART on infection-related cancer. Adjustment for latest HIV RNA level, but not for CD4 cell count or cancer risk factors, attenuated the effect of immediate cART on infection-unrelated cancer.Conclusions. Immediate cART initiation significantly reduces risk of cancer. Although limited by small sample size, this benefit does not appear to be solely attributable to HIV RNA suppression and may be also mediated by other mechanisms.

HIV-Associated Kaposi's Sarcoma

“…In the START trial, in which 4,685 HIV-positive participants with CD4 counts > 500 /μl were randomized either to start cART immediately or to defer therapy until the CD4 count dropped below 350 cells/μl, the reduced risk of infection-related cancer in the immediate arm was mainly driven by a reduction in KS incidence [11]. Similar results were seen in the SMART trial, in which patients on a CD4 T cell-guided cART strategy had a higher incidence of KS lesions during treatment interruptions than patients on continuous cART [12].…”

Combination antiretroviral therapy and cancer risk

“…Recent randomized data indicate that cART reduces risk of KS and NHL also during early HIV infection before the development of overt immunosuppression [••46]. This benefit is measurable in the short term and reported in one trial with relatively short follow up [••46].…”

“…Recent randomized data indicate that cART reduces risk of KS and NHL also during early HIV infection before the development of overt immunosuppression [••46]. This benefit is measurable in the short term and reported in one trial with relatively short follow up [••46]. The long term effect of cART exposure on cancer risk, however, is not well defined and some cohort studies have demonstrated an independent link between long term cART exposure and cancer risk [16, ••17, •18, 47].…”

“…At the individual level, the benefit of immediate cART initiation is evident for a composite endpoint of serious AIDS-defining and non-AIDS-defining events. A closer look into cancer events has also pointed out measurable benefits of immediate cART in reducing cancer risk [••46]. …”

“…Immediate cART initiation reduced the overall risk of cancer by 64% [••77]; corresponding risk reduction figures were 74% for infection-related cancer (Hazard ratios [HR]; 95% confidence interval [CI]: 0.26; 0.11-0.64; p=0.003) and 51% for infection-unrelated cancer (HR; 95% CI: 0.49; 0.21-1.15; p=0.103) [••46]. The benefit of immediate cART initiation in reducing cancer risk was mainly driven by a reduction in cases of KS and NHL.…”