Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk.

TitleMetabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk.
Publication TypeJournal Article
Year of Publication2008
AuthorsTebas P, Henry WKeith, Matining R, Weng-Cherng D, Schmitz J, Valdez H, Jahed N, Myers L, Powderly WG, Katzenstein D
JournalPLoS One
Volume3
Issue4
Paginatione2021
Date Published2008
ISSN1932-6203
KeywordsAntiretroviral Therapy, Highly Active, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Chronic Disease, Glucose, HIV Infections, HIV-1, Humans, Interleukin-2, Lipid Metabolism, Risk Factors
Abstract

BACKGROUND: Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk.

METHODOLOGY: ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count >or=500 cells/microL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/microL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels.

PRINCIPAL FINDINGS: By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (-1.19, -0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (-0.36(-0.73,-0.03)mmol/L, p = 0.0007 and -0.05(-0.26,0.03), p = 0.0033, respectively) and triglycerides decreased (-0.40 (-0.84, 0.07) mmol/L, p = 0.005). However the TC/HDL ratio remained unchanged (-0.09 (-1.2, 0.5), p = 0.2). Glucose and insulin levels did not change (p = 0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (-189, 1655), p = 0.0008) coinciding with the rebound of HIV viremia.

CONCLUSIONS: Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00015704.

DOI10.1371/journal.pone.0002021
Alternate JournalPLoS ONE
PubMed ID18431498
PubMed Central IDPMC2292263
Grant ListAI25868 / AI / NIAID NIH HHS / United States
AI25879 / AI / NIAID NIH HHS / United States
AI25903 / AI / NIAID NIH HHS / United States
AI27661 / AI / NIAID NIH HHS / United States
AI27666 / AI / NIAID NIH HHS / United States
AI39156 / AI / NIAID NIH HHS / United States
AI46370 / AI / NIAID NIH HHS / United States
M01 RR000070 / RR / NCRR NIH HHS / United States
U01AI38858 / AI / NIAID NIH HHS / United States