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Antiviral Therapy 13:177–187
Original article Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial Andrew N Phillips1*, Andrew Carr 2 , Jacquie Neuhaus 3, Fehmida Visnegarwala4, Ronald Prineas5, William J Burman6, Ian Williams7, Fraser Drummond 8, Daniel Duprez 9, Waldo H Belloso10, Frank-Detlef Goebel11, Birgit Grund 3, Angelos Hatzakis12, Jose Vera13 and Jens D Lundgren14 1
Department of Primary Care & Population Sciences, Royal Free & University College Medical School, London, UK St Vincent’s Hospital and University of New South Wales, Sydney, Australia 3 Division of Biostatistics, University of Minnesota, School of Public Health, MN, USA 4 AbsoluteCare Medical Center, Director of Research, Atlanta, GA, USA 5 Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine, WinstonSalem NC, USA 6 Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO, USA 7 Centre for Sexual Health and HIV Research, Royal Free & University College Medical School, London, UK 8 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Australia 9 Cardiovascular Division, University of Minnesota, MN, USA, 10 Infectious Diseases Section, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina 11 Infektionsabteilung, Med. Poliklinik, University of Munich, Germany 12 National Retrovirus Reference Center, Department of Hygiene and Epidemiology, Athens University Medical School, Greece 13 Centro Hospitalar de Cascais, Cascais, Portugal 14 Section on Viral Diseases/KMA, Rigshospitalet and Medical Faculty, University of Copenhagen, Denmark 2
*Corresponding author: E-mail:
[email protected]
Background: The SMART trial found a raised risk of cardiovascular disease (CVD) events in patients undergoing CD4+ T cell-count guided intermittent antiretroviral therapy (ART) compared with patients on continuous ART. Exploratory analyses were performed to better understand the reasons for this observation. Methods: A total of 5,472 patients with CD4+ T-cell counts >350 cells/mm3 were recruited and randomized to either continuous ART (the viral suppression arm; VS) or CD4+ T-cell count-guided use of ART (the drug conservation arm; DC). Results: Major CVD events developed in 79 patients. The hazard ratio (HR) for risk of CVD events for DC versus VS was 1.57 (95% confidence interval 1.00–2.46; P=0.05).
There was no evidence that being off ART or a higher current HIV viral load were associated with increased CVD risk. Total cholesterol and low-density lipoprotein cholesterol were reduced as a result of ART interruption in DC patients but so was high-density lipoprotein (HDL) cholesterol, leading to a net unfavourable change in the total/HDL cholesterol ratio. Conclusions: Reasons for the higher risk of CVD for DC compared with VS patients remain unclear. There was no clear evidence to suggest that ART interruption per se or a higher HIV viral load were associated with an increased CVD risk in the DC group. Lipid changes were less favourable among DC compared with VS patients, which could offer a partial explanation.
Introduction Use of combination antiretroviral therapy (ART) has been shown in cohort studies to be associated with an increased risk of cardiovascular disease (CVD) [1–6]. Increased risk is thought to be partially related © 2008 International Medical Press 1359-6535
to increases in cholesterol levels induced by several antiretroviral drugs [2,7–14]. This observation, together with concerns regarding a number of other potentially serious adverse effects of ART, was a 177
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major factor behind the design of SMART. This randomized study assessed the risks and benefits of reducing ART exposure by using it only intermittently, based on the CD4+ T-cell count. A total of 5,472 patients (of whom 84% were on ART at baseline, 11% ART-experienced but off ART and 5% ART-naive) with CD4+ T-cell count >350 cells/mm3 were randomized to one of two arms: the drug conservation (or DC) arm followed a CD4+ T-cell count-guided intermittent ART strategy involving avoiding or stopping ART when the CD4+ T-cell count was >350 cells/mm3 and (re-) initiating when the CD4+ T-cell count was
