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.

Keywords: HIV; Kaposi sarcoma; antiretroviral therapy; cancer; non-Hodgkin lymphoma.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Figures

Figure 1.

Annual rates of any type of cancer by year of follow-up, stratified by Strategic Timing of Antiretroviral Treatment arm. P value for trend was .026 in the deferred (Def) combination antiretroviral therapy (cART) arm and .790 in the immediate (Imm) cART arm. Abbreviations: ART, antiretroviral therapy; CI, confidence interval; PY, person-years.

Figure 2.

Kaplan–Meier curves giving the cumulative percentage of participants who developed infection-related cancer in each Strategic Timing of Antiretroviral Treatment arm. Abbreviations: ART, antiretroviral therapy; Def, deferred; Imm, immediate; pts, patients.

Figure 3.

Kaplan–Meier curves giving the cumulative percentage of participants who developed infection-unrelated cancer in each Strategic Timing of Antiretroviral Treatment arm. Abbreviations: ART, antiretroviral therapy; Def, deferred; Imm, immediate; pts, patients.

Figure 4.

Factors independently associated with infection-related and infection-unrelated cancer. Hepatitis B/C could not be estimated for infection-related cancer. Abbreviations: BMI, body mass index; CI, confidence interval; HIV, human immunodeficiency virus.

Figure 5.

Immediate vs deferred combination antiretroviral therapy (cART) initiation and the risk of any type, infection-related and infection-unrelated cancer in the Strategic Timing of Antiretroviral Treatment (START) study. 1Infection-related cancer: human herpesvirus 8 (Kaposi sarcoma), Epstein-Barr virus (non-Hodgkin lymphoma, Hodgkin lymphoma), human papillomavirus (anal cancer, cervical cancer); 2Infection-unrelated cancer: prostate cancer, lung cancer, testis cancer, plasma cell myeloma, fibrosarcoma, breast cancer, bladder cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid cancer, leiomyosarcoma, squamous cell carcinoma of the head and neck, squamous cell cancer, gastric adenocarcinoma, liver cancer. Models: (A) Univariable, estimated in a Cox proportional hazards model with a single treatment indicator. (B) Adjusted for baseline covariates: age, sex, race, geographical region, smoking, body mass index, hepatitis B/C, baseline CD4 cell count, and baseline log10 human immunodeficiency virus (HIV) RNA. (C) Adjusted for latest CD4 cell count, modeled as a continuous variable. (D) Adjusted for latest HIV RNA, modeled as ≤200 copies/mL vs >200 copies/mL. (E) Adjusted for latest CD4 cell count and latest HIV RNA. (F) As in (B) with further adjustment for latest CD4 cell count and latest HIV RNA. (G) Adjusted for latest log10 HIV RNA. (H) Adjusted for latest CD4:CD8 ratio. Abbreviation: CI, confidence interval.