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Strategic Timing of ART to Prevent Morbidity and Mortality
- 1. Strategic Timing of Antiretroviral Treatment Community Slides INSIGHT Washington ICC August 2011
- 2. Strategic Timing of Antiretroviral Treatment STUDY RATIONALE
- 3. Pantaleo G, et al. N Engl J Med 1993 The Natural History of HIV Infection
- 4. Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases
- 5. Unexpected results from SMART led to a new way of thinking about non-AIDS events. The findings from SMART motivate START.
- 6. SMART: Severe Complications Endpoint and Components No. of Patients with Events Subgroups Severe Complications 114 Non-Fatal CVD Events 63 Non-Fatal Hepatic Events 14 Non-Fatal Renal Events 7 Favors VS ► Relative Risk (95% CI) 1.5 1.5 1.4 2.5 1.4 CVD, Liver, or Renal Deaths 31 > ► Favors DC
- 7. Selected Publications on Non-AIDS Events
- 8. Evolution of Focus of Concern Opportunistic infections & malignancies CMV PCP MAC Toxoplasmosis Cryptococcosis Candidiasis Histoplasmosis Kaposi Sarcoma Complications of therapy CVD Metabolic Renal Hepatic Neurologic Hematologic Serious, non-AIDS morbidities MI Stroke Renal Failure Hepatic Failure Malignancies Time
- 9. A New Paradigm: Time in Years Infection CD4+ cells 1000 800 600 400 200 0 Early Opportunistic Infections Late Opportunistic Infections 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Ongoing Morbidity from HIV The Broader Spectrum of HIV Disease
- 10. Would Earlier ART Prevent Morbidity and Mortality in HIV?
- 11. Shifting recommendations for “When to start ART” – IAS USA panel, 1996-2010 > 500 VL>5K VL>10K 350-500 VL>5K VL>5K 200-350 <200 CD4 1996 1998 2000 2002 2004 2006 2008 2010
- 12. When to start ART? Summary of Current Guidelines For asymptomatic patients CD4 <350 CD4 350-500 CD4 >500 EACS, 2009 treat defer W/ SPECIAL CONSIDERATIONS defer US DHHS, 2011 treat treat No consensus WHO 2010 treat --- ---
- 15. SMART subset analyses A subset of SMART participants not on ART at baseline were examined; this analysis further informed the design of START Drug Conservation (DC) Strategy Virologic Suppression (VS) Strategy Patients not on ART at baseline (n=477) Immediate ART (n=249) Deferred ART until CD4+ < 250 (n=228)
- 20. Strategic Timing of Antiretroviral Treatment PROTOCOL OVERVIEW
- 21. START Design HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 Early ART Group Initiate ART immediately following randomization N=2,000 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,000
- 31. Initial ART Regimens in START As of 14 January 2010 To Construct an Antiretroviral Regimen, Select 1 Component from Column A + 1 from Column B Column A (NNRTI or PI or Integrase Inhibitor Options) + Column B (Dual-NRTI Options) NNRTI PI efavirenz OR atazanavir + ritonavir (1x/day) darunavir + ritonavir (1x/day) fosamprenavir + ritonavir (2x/day) fosamprenavir + ritonavir (1x/day) lopinavir/ritonavir (2x/day) lopinavir/ritonavir (1x/day) OR Integrase Inhibitor (II) raltegravir (2x/day) abacavir/lamivudine tenofovir/emtricitabine zidovudine/lamivudine
- 34. Strategic Timing of Antiretroviral Treatment A Multicenter Study by INSIGHT – International Network for Strategic Initiatives in Global HIV Research START SUBSTUDIES
- 37. Genomics Substudy Open to all participating sites
- 40. Informed Consent Substudy Open to all participating sites
- 45. Neurology Substudy At 36 participating sites
- 46. START Neurology Substudy HIV-infected, ARV naïve, CD4+ cell counts > 500 cells/mm 3 Co-enrolled in START Study N=600 Early ART Group N=300 Immediately initiate ART Deferred ART Group N=300 Defer ART until CD4+ <350 cells/mm 3 or symptoms develop
- 52. Arterial Elasticity Substudy At 24 participating sites
- 55. Blood Pressure Waveform Analysis (via peripheral pulse)
- 58. Pulmonary Substudy At 91 participating sites
- 60. HIV and COPD Hypothesis: In patients with HIV infection (ART-naïve and with CD4>500), immediate ART slows the rate of FEV 1 decline compared to deferral of ART until the CD4 declines to <350. Plan: Test this hypothesis with a randomized, controlled trial, as a substudy in the Strategic Timing of Antiretroviral Therapy (START) trial. Specific Aim 1: In a subsample of 1,000 START trial participants, compare the immediate and deferred ART groups for rate of decline of forced expiratory volume in one second (FEV 1 ) over a 3 to 5 year follow-up period, separately for smokers and non-smokers . Unknown: Does ART change the rate of FEV 1 decline in patients with HIV infection? “ Disease Modification”
- 63. Bone Mineral Density Substudy At 43 participating sites
- 64. Bone Mineral Density Substudy HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 N=400 Early ART Group Initiate ART immediately following randomization N=200 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=200
- 69. Malignancy Tissue Collection At all participating sites
Notas del editor
- Changes based on an increasing number and increasingly sophisticated observational cohort studies, aspects of the immunopathogenesis of HIV, concerns about toxicity of ART
- Patients will be coenrolled at selected, geographically diverse sites Randomisation will be determined by the parent study Patients will be followed to the common closing date of the START study
- The picture of the Birds of New Guinea represents the Verbal Fluency test where patients will be asked, among other things, to give as many names of different types of animals as possible within 1 minute
- With respect to assessment of damage to endothelial surfaces and vascular disease before patients present with clinical events (such as a myocardial infarction), there are several surrogate markers that have been associated with atherosclerotic risk as well as true disease. The premise for using these methods is based on the general pathogenesis model again laid out at the bottom of the screen Most of the listed methods for assessing functional and structural changes in the vasculature have been studied in persons with HIV infection, and each reflects abnormalities at a different stage along the temporal continuum of vascular disease
- One useful approach to characterize arterial stiffness, or elasticity (1/stiffness), is via analysis of the blood pressure waveform. The contour of the BP waveform can provide information related to structural and functional characteristics of the aorta, muscular conduit arteries, the peripheral branches, and the micro-vascular component. Analysis of the systolic portion of the BP waveform… e.g., augmentation index (AIx) -Peripheral AI = P2/P1 -Central AI = Augmented pressure / pulse pressure Analysis of the diastolic portion of the BP waveform is the focus of methods used in AE substudy (HDI/CR2000 PulseWave) -Modified Windkessel model that examines the circulatory system as an electrical circuit, with 2 capacitance elements (representing the large and small artery pools) - A typical waveform will have two maxima present within the diastolic decay curve. The first occurs at the beginning of diastole and represents the capacitance of the proximal aorta and major branches following cardiac ejection. The second maximum results from a rebound wave, reflecting elasticity in the smaller arteries.
- There are 3 main components of AE substudy visits…
- We think ART will be good for the lungs, but this trial aims to determine if ART is good or bad for the lungs.
- BOLD collaborative has shared some of their experiences with us to help us plan for the START Pulmonary Substudy. PLATINO group may be able to assist Latin American sites.
- Osteopenia refers to an early state of bone loss where a person’s bone mineral density (BMD)-a measurement that determines bone density and strength-is lower than normal peak BMD, but not low enough to be classified as osteoporosis. A diagnosis of osteopenia means that there is a greater risk for developing osteoporosis later on, but not everyone diagnosed with osteopenia develops osteoporosis. As a result, doctors do not view osteopenia as a disease, but as a potential marker for further bone loss and fracture.