Starting antiretroviral therapy (ART) immediately in the international START trial lowered the risk of incident infection-related cancer almost 75% but did not significantly affect risk of infection-unrelated cancer. This infection-related cancer benefit could not be attributed solely to HIV RNA suppression.
HIV populations have higher cancer rates than comparable general population groups. As people live longer with HIV, cancer has become a major cause of morbidity and mortality. The 35-country START trial randomized HIV-positive people with a CD4 count above 500 cells/mm3 to immediate ART or to defer treatment until their CD4 count fell to 350 cells/mm3 or an AIDS illness developed. Immediate ART lowered overall cancer risk by 64%, even though START participants had a median age of 36 years and a median baseline CD4 count of 651 cells/mm3.
The new analysis tracked new diagnoses of infection-related cancer and infection-unrelated cancer in the two START study arms, which included 4685 participants. START investigators used multivariable Cox models to identify factors independently associated with risk of infection-related cancer or infection-unrelated cancer. To identify mediators of reduced cancer risk in the immediate-ART group, the researchers used Cox proportional hazards models adjusted sequentially for demographics, traditional cancer risk factors, and baseline and time-updated HIV-related variables.
Through an average three years of follow-up, 14 malignancies developed in the immediate ART arm (six infection-related and eight infection-unrelated), while 39 developed in the deferred arm (23 infection-related and 16 infection-unrelated). Median age was 36 years in 4632 participants without cancer, 44 in 29 participants with infection-related cancer and 51 in 24 participants with infection-unrelated cancer. Median initial CD4 counts in those three groups were 651, 671 and 638 cells/mm3
Incidence of infection-related cancer was 74% lower in the immediate-ART arm than the deferred arm (hazard ratio [HR] 0.26, 95% confidence interval 0.11 to 0.64, P = .003). A 51% lower risk of infection-unrelated cancer in the immediate arm did not reach statistical significance (HR 0.49, 95% CI 0.21 to 1.15, P = .103).
Analysis of the combined immediate and deferred arms identified five independent baseline predictors of infection-related cancer: older age (HR 1.42 per 10 years older, 95% confidence interval [CI] 0.99 to 2.02), higher body mass index (HR 1.47 per 5 kg/m2, 95% CI 1.05 to 2.05), low- to middle-income region (HR 3.40, 95% CI 1.44 to 8.02), higher baseline HIV RNA (HR 2.01 per 1 log10 higher, 95% CI 1.17 to 3.47) and higher baseline CD8 count (HR 1.13 per 200 cells/mm3 higher, 95% CI 1.03 to 1.24). Two factors independently predicted infection-unrelated cancer: older age (HR 2.54 per 10 years older, 95% CI 1.72 to 3.73) and higher baseline CD8 count (HR 1.12 per 200 cells/mm3 higher, 95% CI 1.01 to 1.25).
Sequential adjustment for demographics, traditional cancer risk factors and CD4 count had no impact on estimates of cancer risk. Adjustment for latest HIV RNA and (additionally) for CD4:CD8 ratio partially attenuated the protective effect of immediate ART on any cancer type and on infection-related cancer.
Because of this attenuating impact of latest HIV RNA on cancer risk, the START team suggested that the protective effect of immediate ART might also be mediated by other mechanisms, "such as a curb on oncogenic virus coinfection and reduction of inflammation." The researchers determined that reduced incidence of Kaposi sarcoma and non-Hodgkin lymphoma largely accounted for the effect of immediate ART on infection-related cancers. The investigators call their findings unexpected because START enrolled patients at an early stage of HIV infection and follow-up was shorter than planned.
Mark Mascolini writes about HIV infection.