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Strategic Timing  of Antiretroviral Treatment   Community Slides INSIGHT Washington ICC August 2011
Strategic Timing  of Antiretroviral Treatment   STUDY RATIONALE
Pantaleo G, et al. N Engl J Med 1993 The Natural History of HIV Infection
Natural History of HIV:  Focus on  Advanced HIV and Opportunistic Diseases
Unexpected results from SMART led to a new way of thinking about non-AIDS events.  The findings from SMART motivate START.
SMART: Severe Complications  Endpoint and Components No. of Patients with Events Subgroups Severe Complications 114 Non-Fa...
Selected Publications on Non-AIDS Events
Evolution of  Focus of Concern Opportunistic infections & malignancies CMV PCP MAC Toxoplasmosis Cryptococcosis Candidiasi...
A New Paradigm:   Time in Years Infection CD4+ cells 1000 800 600 400 200 0 Early Opportunistic Infections Late Opportunis...
Would Earlier ART  Prevent Morbidity and Mortality in HIV?
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...
When to start ART? Summary of Current Guidelines For asymptomatic patients CD4  <350 CD4  350-500 CD4  >500 EACS, 2009 tre...
2011 US Guidelines <ul><li>“ Randomized controlled trials provide evidence supporting the benefit of antiretroviral therap...
Evidence from Randomized Trials for Initiating Treatment at CD4 200-350  <ul><li>CIPRA-HT001  – a single center trial in H...
SMART subset analyses A subset of SMART participants not on ART at baseline were examined; this analysis further informed ...
Continuous use of ART Associated with decreased rate of serious non-AIDS Events in Subset of Patients Naïve or  on no ART ...
Evidence from Observational Studies for Initiating ART with CD4 > 350 <ul><li>Comparison  CD4+ count strata   HR for death...
Evidence from HPTN 052: ART prevents HIV transmission <ul><li>1763 discordant couples (one HIV-infected partner) </li></ul...
Evidence Needed to Guide Decisions on  Individual Patient  Management <ul><li>Benefit of early HIV treatment on serious cl...
Strategic Timing  of Antiretroviral Treatment   PROTOCOL OVERVIEW
START Design   HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 Early ART Group Initiate ART im...
Inclusion   Criteria <ul><li>Signed informed consent </li></ul><ul><li>Documentation of HIV infection </li></ul><ul><li>Ag...
Exclusion Criteria <ul><li>Any previous ART or IL-2 </li></ul><ul><li>Diagnosis of any clinical AIDS event </li></ul><ul><...
Primary Study Endpoint (Time to first event) <ul><li>AIDS* or death from AIDS </li></ul><ul><ul><li>Opportunistic events c...
Secondary Endpoints (1) <ul><li>Individual components of composite primary endpoint </li></ul><ul><li>Bacterial pneumonia ...
Secondary Endpoints (2) <ul><li>Pulmonary embolism or deep vein thrombosis </li></ul><ul><li>New-onset diabetes mellitus <...
Sample Size for Definitive Study <ul><li>90% power and alpha = 0.05 (2-sided)  N = 4,000  </li></ul><ul><li>Hypothesized r...
A Two-Phased Approach for START <ul><li>Pilot Phase  to Assess Feasibility:  Completed </li></ul><ul><ul><li>Establish tha...
START Collaboration with Pharma <ul><li>Abbott: Ritonavir, Lopinavir/Ritonavir  (tablets for both in 2012) </li></ul><ul><...
ART in START <ul><li>ART must be from one of two sources: </li></ul><ul><li>-- INSIGHT repository </li></ul><ul><li>-- FDA...
Initial ART Regimens in START As of 14 January 2010 To Construct an Antiretroviral Regimen,  Select 1 Component from Colum...
START STUDY Funding <ul><li>Division of AIDS, The National Institute of Allergy and Infectious  </li></ul><ul><li>Diseases...
START Study Definitive Phase 4 ICCs – 36 Countries – 240 Sites  Washington ICC Sydney ICC Copenhagen ICC London ICC Brazil...
Strategic Timing  of Antiretroviral Treatment   A Multicenter Study by INSIGHT – International Network for Strategic Initi...
START Substudies <ul><li>Genomics   (NIAID, NCI) </li></ul><ul><li>Informed Consent  (NIH Clinical Bioethics Dept.) </li><...
START Substudies <ul><li>A means to maximize scientific gain from the effort </li></ul><ul><li>Funding from a variety of s...
Genomics Substudy Open to all participating sites
Study Purpose <ul><li>“… to obtain a whole blood sample from which DNA will be extracted to study validated (present and f...
Study Design <ul><li>Nonrandomized multicenter study </li></ul><ul><li>Maximum of all START participants  </li></ul><ul><l...
Informed Consent Substudy  Open to all participating sites
START Informed Consent Substudy <ul><li>Purpose </li></ul><ul><li>To compare  understanding  of study information and  sat...
Informed Consent Substudy Background <ul><li>Consent forms for clinical trials are often long, technical, and legalistic. ...
Informed Consent Substudy Hypothesis <ul><li>Comprehension  of essential study information among participants in the conci...
Informed Consent Substudy Consent Forms <ul><li>Each consent form contains information needed to make a decision about par...
Neurology Substudy At 36 participating sites
START Neurology Substudy  HIV-infected, ARV naïve,  CD4+ cell counts > 500 cells/mm 3 Co-enrolled in START Study  N=600 Ea...
START Neurology Substudy <ul><li>Hypothesis </li></ul><ul><ul><li>Patients randomised to early ART will have superior neur...
How are HIV-1 Associated Neurocognitive Disorders (HAND) now classified? <ul><li>ANSWER </li></ul><ul><li>Asymptomatic Neu...
START Neurology Substudy <ul><li>Inclusion criteria </li></ul><ul><ul><li>Simultaneous co-enrollment in the START Study </...
Measures of Neurocognitive Functioning <ul><li>Quantitative QNPZ-8 score </li></ul><ul><ul><li>Color Trails 1  and 2  </li...
Study Endpoints <ul><li>Primary Endpoint </li></ul><ul><ul><li>Change in QNPZ-8 scores </li></ul></ul><ul><li>Secondary En...
Arterial Elasticity Substudy At 24 participating sites
START Arterial Elasticity Substudy <ul><li>Purpose :  To determine if participants randomized to early ART will have incre...
Atherosclerotic Risk and Disease:  Surrogate Non-invasive Markers  <ul><li>Structural Assessment </li></ul><ul><li>Carotid...
Blood Pressure Waveform Analysis (via peripheral pulse)
CR-2000 System Components <ul><li>The Cardiovascular Profiling Instrument </li></ul><ul><li>Main Electrical Power Cord (Ho...
AE Substudy Visit Procedures:  1)  BP waveform analysis <ul><li>Participant lying supine </li></ul><ul><li>Wrist stabilize...
Pulmonary Substudy  At 91 participating sites
START Pulmonary Substudy HIV-infected patients with CD4+ counts >500 cells/mm 3 n = 1,000 (91 sites) Early ART group Initi...
HIV and COPD Hypothesis:  In patients with HIV infection (ART-naïve and with CD4>500), immediate ART slows the rate of FEV...
Spirometry <ul><li>Simple setup, no calibration, portable </li></ul><ul><li>Disposable patient interface (no complex clean...
Summary <ul><li>HIV is an independent risk factor for COPD </li></ul><ul><li>The effect of ART on COPD risk / lung functio...
Bone Mineral Density Substudy  At 43 participating sites
Bone Mineral Density Substudy  HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 N=400 Early ART...
Low Bone Mineral Density (BMD) Osteopenia and Osteoporosis <ul><li>Bone mineral density is a measurement of the level of m...
Hypotheses <ul><li>Primary </li></ul><ul><ul><li>The early ART group will have more BMD loss than the deferred ART group. ...
Inclusion criteria <ul><li>Simultaneous co-enrollment in the START study. </li></ul><ul><li>Signed informed consent to the...
Exclusion criteria <ul><li>Inability to obtain valid BMD measurements from DXA scans, e.g., because of any of the followin...
Malignancy Tissue Collection  At all participating sites
START Malignancy Tissue Sample Collection <ul><li>Purpose :  To collect a biopsy tissue and blood sample from participants...
<ul><li>For latest START accrual & other study info, check out the INSIGHT website: </li></ul><ul><li>www.insight-trials.o...
 
Time to START <ul><li>START is a critically important randomized trial that will assess the benefits and risks of early tr...
 
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Start study slides_dc_icc_ccg_11-aug-11

  1. 1. Strategic Timing of Antiretroviral Treatment Community Slides INSIGHT Washington ICC August 2011
  2. 2. Strategic Timing of Antiretroviral Treatment STUDY RATIONALE
  3. 3. Pantaleo G, et al. N Engl J Med 1993 The Natural History of HIV Infection
  4. 4. Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases
  5. 5. Unexpected results from SMART led to a new way of thinking about non-AIDS events. The findings from SMART motivate START.
  6. 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. 7. Selected Publications on Non-AIDS Events
  8. 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. 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. 10. Would Earlier ART Prevent Morbidity and Mortality in HIV?
  11. 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. 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 --- ---
  13. 13. 2011 US Guidelines <ul><li>“ Randomized controlled trials provide evidence supporting the benefit of antiretroviral therapy in patients with CD4 counts of 350 cells/mm 3 or less. However, such evidence showing benefit for patients with higher CD4 cell counts is not yet available …” </li></ul>
  14. 14. Evidence from Randomized Trials for Initiating Treatment at CD4 200-350 <ul><li>CIPRA-HT001 – a single center trial in Haiti </li></ul><ul><li>2/3 of patients were clinical stage 2 or 3 and the median CD4+ count at initiation in the deferred ART group was 166 cells/mm 3 (IQR: 130, 190). </li></ul><ul><li>A post-hoc analysis of the SMART Study </li></ul><ul><li>Only involved 477 patients and of these only 249 were ART-naïve. </li></ul><ul><li>HPTN 052 </li></ul><ul><li>Deferral strategy was 200-250 cells; significant difference in extrapulmonary TB; not powered to address survival (10 versus 13 deaths). </li></ul>
  15. 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)
  16. 16. Continuous use of ART Associated with decreased rate of serious non-AIDS Events in Subset of Patients Naïve or on no ART for > 6 Months at Entry in SMART DC Group VS Group HR (DC/VS) Deferred vs. Early P-value N Rate N Rate 95% CI <ul><li>OD or death 15 4.8 4 1.1 4.4 [1.5, 13.2] 0.009 </li></ul><ul><li>OD fatal or non-fatal 11 3.5 3 0.8 4.4 [1.2, 15.8] 0.02 </li></ul><ul><li>Serious non-AIDS 12 3.9 2 0.5 7.1 [1.6, 31.5] 0.01 </li></ul><ul><li>Composite 21* 7.0 5 1.3 5.1 [1.9, 13.5] 0.001 </li></ul>Emery et al, JID, April 2008
  17. 17. Evidence from Observational Studies for Initiating ART with CD4 > 350 <ul><li>Comparison CD4+ count strata HR for death </li></ul><ul><li>NA ACCORD <350 vs 350-500 1.7 (1.3 - 2.3) </li></ul><ul><li> 350-500 vs > 500 1.9 (1.4 – 2.8) </li></ul><ul><li>ART CC 251-350 vs 351-450 1.1 (0.8 - 1.6) </li></ul><ul><li>351-450 vs 451-550 0.9 (0.6 - 1.4) </li></ul><ul><li>HIV-Causal 350 vs 500 1.0 (0.8-1.2) </li></ul><ul><li>Kitahata MM et al, N Engl J Med 2009 </li></ul><ul><li>When to Start Consortium, Lancet 2009 </li></ul><ul><li>HIV Causal Collaboration, Annals Int Med, 2011 </li></ul>
  18. 18. Evidence from HPTN 052: ART prevents HIV transmission <ul><li>1763 discordant couples (one HIV-infected partner) </li></ul><ul><li>Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, Zimbabwe (+ single US couple) </li></ul><ul><li>CD4 count at entry: 350 – 550 cells/mm ₃ </li></ul><ul><li>Index case randomized to IMMEDIATE ART vs DEFERRED ART </li></ul><ul><li>Deferral until CD4 count drops to < 250 cells/mm ₃ or disease </li></ul><ul><li>RESULTS: </li></ul><ul><li>1 new HIV infection in partners of those on ART </li></ul><ul><li>27 new HIV infections in partners of those deferring ART </li></ul><ul><li>96% efficacy of ART to prevent transmission in this population </li></ul>
  19. 19. Evidence Needed to Guide Decisions on Individual Patient Management <ul><li>Benefit of early HIV treatment on serious clinical events (AIDS & non-AIDS) </li></ul><ul><li>Effect of early HIV treatment on: </li></ul><ul><ul><li>Metabolic abnormalities </li></ul></ul><ul><ul><li>Body composition </li></ul></ul><ul><ul><li>Adverse events </li></ul></ul><ul><ul><li>Resistance </li></ul></ul><ul><ul><li>Adherence & regimen use </li></ul></ul><ul><ul><li>Cost </li></ul></ul>
  20. 20. Strategic Timing of Antiretroviral Treatment PROTOCOL OVERVIEW
  21. 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
  22. 22. Inclusion Criteria <ul><li>Signed informed consent </li></ul><ul><li>Documentation of HIV infection </li></ul><ul><li>Age ≥ 18 years </li></ul><ul><li>Karnofsky performance score ≥ 80 </li></ul><ul><li>Perceived life expectancy of at least 6 months </li></ul><ul><li>For women of childbearing potential, willingness to use contraceptives as described in the product information of the ART drugs they are prescribed </li></ul><ul><li>Two CD4+ cell counts > 500 cells/mm 3 at least 2 weeks apart </li></ul>
  23. 23. Exclusion Criteria <ul><li>Any previous ART or IL-2 </li></ul><ul><li>Diagnosis of any clinical AIDS event </li></ul><ul><li>Presence of HIV progression such as oral thrush, unexplained weight loss, or unexplained fever </li></ul><ul><li>Within 6 months prior to randomization, any of the following: </li></ul><ul><ul><li>Cardiovascular event (MI, angioplasty, CABG, stroke) </li></ul></ul><ul><ul><li>Non-AIDS-defining cancer (excluding basal and squamous cell skin cancer) </li></ul></ul><ul><ul><li>Dialysis </li></ul></ul><ul><li>History of decompensated liver disease </li></ul><ul><li>Current imprisonment or compulsory detention (involuntary incarceration) for treatment of a psychiatric or physical illness </li></ul><ul><li>Current pregnancy or breastfeeding </li></ul>
  24. 24. Primary Study Endpoint (Time to first event) <ul><li>AIDS* or death from AIDS </li></ul><ul><ul><li>Opportunistic events consistent with the 1993 CDC expanded surveillance definition, plus additional events. *Esophageal candidiasis and chronic Herpes simplex counted only if they result in death. </li></ul></ul><ul><li>Non-AIDS </li></ul><ul><ul><li>Cardiovascular disease (CVD) (MI, angioplasty, CABG, stroke) </li></ul></ul><ul><ul><li>Chronic end-stage renal disease (ESRD) (initiation of dialysis, renal transplantation) </li></ul></ul><ul><ul><li>Decompensated liver disease </li></ul></ul><ul><ul><li>Non-AIDS defining cancers (basal and squamous cell skin cancers are not counted) </li></ul></ul><ul><li>Death not attributable to AIDS, including death of </li></ul><ul><li>unknown cause </li></ul>
  25. 25. Secondary Endpoints (1) <ul><li>Individual components of composite primary endpoint </li></ul><ul><li>Bacterial pneumonia </li></ul><ul><li>Adverse events </li></ul><ul><li>Hospitalization </li></ul><ul><li>Quality of life </li></ul><ul><li>Health care utilization and cost of care </li></ul><ul><li>HIV transmission risk behavior </li></ul><ul><li>HIV drug resistance </li></ul>
  26. 26. Secondary Endpoints (2) <ul><li>Pulmonary embolism or deep vein thrombosis </li></ul><ul><li>New-onset diabetes mellitus </li></ul><ul><li>Coronary artery disease requiring drug treatment </li></ul><ul><li>Congestive heart failure </li></ul><ul><li>Peripheral arterial disease </li></ul><ul><li>Change in estimated GFR and development of proteinuria </li></ul><ul><li>Blood pressure and blood lipids </li></ul><ul><li>ECG abnormalities </li></ul><ul><li>Use of BP- or lipid-lowering treatment or aspirin </li></ul>
  27. 27. Sample Size for Definitive Study <ul><li>90% power and alpha = 0.05 (2-sided) N = 4,000 </li></ul><ul><li>Hypothesized risk reductions with early ART (compared to no ART) are: </li></ul><ul><ul><li>AIDS* = 43% </li></ul></ul><ul><ul><li>Serious non-AIDS = 24% </li></ul></ul><ul><ul><li>Composite of AIDS* (20% of events) and non-AIDS (80% of events) = 28.8% </li></ul></ul><ul><li>Rate in deferred ART group for composite outcome = 2.8 per 100 person years </li></ul><ul><li>4.5 years average follow-up </li></ul><ul><li>Loss to follow-up rate of 2.7 per 100 person years, equivalent to 15% cumulative lost to follow-up after 6 years </li></ul><ul><li>Hypothesized hazard ratio after considering use of ART in the deferred arm and non-adherence in early ART arm = 0.71 </li></ul><ul><li>Target number of primary events = 370 , of which 74 are fatal and non-fatal AIDS* and 296 are fatal and non-fatal non-AIDS events </li></ul>
  28. 28. A Two-Phased Approach for START <ul><li>Pilot Phase to Assess Feasibility: Completed </li></ul><ul><ul><li>Establish that the trial can be enrolled </li></ul></ul><ul><ul><li>Demonstrate excellent follow-up and protocol adherence </li></ul></ul><ul><li>Definitive Trial : N = 4,000 (est.) Ongoing </li></ul><ul><ul><li>Enroll additional participants </li></ul></ul><ul><ul><li>Estimate event rate in the deferred arm and the fraction of events that are non-AIDS </li></ul></ul><ul><ul><li>Re-estimate sample size in mid-2012 </li></ul></ul><ul><ul><li>Follow all participants, including those enrolled in pilot phase, for 3 – 5 more years (est. December 2015) </li></ul></ul>
  29. 29. START Collaboration with Pharma <ul><li>Abbott: Ritonavir, Lopinavir/Ritonavir (tablets for both in 2012) </li></ul><ul><li>Bristol-Myers Squibb: Efavirenz, Atazanavir, Atripla ® </li></ul><ul><li>Gilead: Truvada, Atripla ® </li></ul><ul><li>GlaxoSmithKline: Fosamprenavir, Combivir ® , Epzicom ® </li></ul><ul><li>Merck: Efavirenz, Raltegravir (available mid-2011) </li></ul><ul><li>Tibotec: Darunavir </li></ul>
  30. 30. ART in START <ul><li>ART must be from one of two sources: </li></ul><ul><li>-- INSIGHT repository </li></ul><ul><li>-- FDA-approved or tentatively approved drugs available locally (eg. from Global Fund sources) </li></ul><ul><li>Initial ART Regimen prescribed must be from INSIGHT Web Table </li></ul><ul><li>Clinicians may choose subsequent regimens from among all available approved drugs </li></ul>
  31. 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
  32. 32. START STUDY Funding <ul><li>Division of AIDS, The National Institute of Allergy and Infectious </li></ul><ul><li>Diseases (NIAID), National Institutes of Health (NIH) PRIMARY FUNDER </li></ul><ul><li>Other NIH support: </li></ul><ul><li>-Department of Bioethics, The Clinical Center </li></ul><ul><li>-Division of Clinical Research (NIAID) </li></ul><ul><li>-National Cancer Institute (NCI) </li></ul><ul><li>-National Heart, Lung, and Blood Institute (NHLBI) </li></ul><ul><li>-National Institute of Child Health and Human Development (NICHD) </li></ul><ul><li>-National Institute of Mental Health (NIMH) </li></ul><ul><li>-National Institute of Neurological Disorders and Stroke (NINDS) </li></ul><ul><li>-National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) </li></ul><ul><li>Agence Nationale de Recherches sur le SIDA et les Hépatites Virales </li></ul><ul><li>(ANRS, France) </li></ul><ul><li>Bundesministerium für Bildung und Forschung  (BMBF, Germany) </li></ul><ul><li>NEAT - European AIDS Treatment Network </li></ul><ul><li>Australian National Health and Medical Research Council (NHMRC) </li></ul><ul><li>National Institute for Health Research, UK </li></ul><ul><li>Medical Research Council, UK </li></ul><ul><li>University of Minnesota </li></ul>
  33. 33. START Study Definitive Phase 4 ICCs – 36 Countries – 240 Sites Washington ICC Sydney ICC Copenhagen ICC London ICC Brazil Mali Peru South Africa United States Argentina Australia Chile India Israel Malaysia Mexico Nigeria Singapore Thailand <ul><ul><li>Austria </li></ul></ul><ul><ul><li>Belgium </li></ul></ul><ul><ul><li>Czech Rep. </li></ul></ul><ul><ul><li>Denmark </li></ul></ul><ul><ul><li>Estonia </li></ul></ul><ul><ul><li>Finland </li></ul></ul><ul><ul><li>Germany </li></ul></ul><ul><ul><li>Luxembourg </li></ul></ul><ul><ul><li>Norway </li></ul></ul><ul><ul><li>Poland </li></ul></ul><ul><ul><li>Portugal </li></ul></ul><ul><ul><li>Spain </li></ul></ul><ul><ul><li>Sweden </li></ul></ul><ul><ul><li>France </li></ul></ul><ul><ul><li>Greece </li></ul></ul><ul><ul><li>Ireland </li></ul></ul><ul><ul><li>Italy </li></ul></ul><ul><ul><li>Morocco </li></ul></ul><ul><ul><li>Switzerland </li></ul></ul><ul><ul><li>Uganda </li></ul></ul><ul><ul><li>United Kingdom </li></ul></ul>
  34. 34. Strategic Timing of Antiretroviral Treatment A Multicenter Study by INSIGHT – International Network for Strategic Initiatives in Global HIV Research START SUBSTUDIES
  35. 35. START Substudies <ul><li>Genomics (NIAID, NCI) </li></ul><ul><li>Informed Consent (NIH Clinical Bioethics Dept.) </li></ul><ul><li>Neurology (NIMH, NINDS) </li></ul><ul><li>Arterial Elasticity (NHLBI) </li></ul><ul><li>Pulmonary Function (NHLBI) </li></ul><ul><li>Bone Mineral Density (NIAMS) </li></ul><ul><li>Malignancy Tissue Collection (NCI) </li></ul>
  36. 36. START Substudies <ul><li>A means to maximize scientific gain from the effort </li></ul><ul><li>Funding from a variety of sources </li></ul><ul><li>An opportunity for a broader group of investigators to become involved </li></ul><ul><li>Some substudies open at all sites – some at selected sites – based in part on sample size </li></ul><ul><li>Each site needs to balance appeal of substudy to staff and patients with workload issues </li></ul><ul><li>Additional substudies may be added </li></ul>
  37. 37. Genomics Substudy Open to all participating sites
  38. 38. Study Purpose <ul><li>“… to obtain a whole blood sample from which DNA will be extracted to study validated (present and future) genetic variants that determine the risk of the various primary and secondary outcomes assessed in START.” </li></ul>
  39. 39. Study Design <ul><li>Nonrandomized multicenter study </li></ul><ul><li>Maximum of all START participants </li></ul><ul><li>Open to all sites </li></ul><ul><li>Inclusion criteria </li></ul><ul><ul><li>Consent to randomization in START </li></ul></ul><ul><ul><li>Signed informed consent for the substudy </li></ul></ul><ul><li>Exclusion criteria </li></ul><ul><ul><li>None </li></ul></ul>
  40. 40. Informed Consent Substudy Open to all participating sites
  41. 41. START Informed Consent Substudy <ul><li>Purpose </li></ul><ul><li>To compare understanding of study information and satisfaction with the consent process among START research participants, after receiving information from one of two different types of consent form, a standard consent and a concise consent. </li></ul>
  42. 42. Informed Consent Substudy Background <ul><li>Consent forms for clinical trials are often long, technical, and legalistic. </li></ul><ul><li>Data show that research participants have limited understanding of study information </li></ul><ul><li>The INSIGHT START study presents an opportunity to compare participant understanding, after a standard or concise consent form, across multiple settings and in multiple languages </li></ul>
  43. 43. Informed Consent Substudy Hypothesis <ul><li>Comprehension of essential study information among participants in the concise consent group will be at least as good as that of participants in the standard consent group. </li></ul><ul><li>Satisfaction with the process will be higher for the concise group. </li></ul>
  44. 44. Informed Consent Substudy Consent Forms <ul><li>Each consent form contains information needed to make a decision about participating in START and all the required elements of informed consent from 45CFR46.116 and 21CFR50.25 * </li></ul><ul><li>Both consent forms tell participants that they are participating in this substudy, and that they will only get one of the forms </li></ul><ul><li>* CFR = United States Code of Federal Regulations </li></ul>
  45. 45. Neurology Substudy At 36 participating sites
  46. 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
  47. 47. START Neurology Substudy <ul><li>Hypothesis </li></ul><ul><ul><li>Patients randomised to early ART will have superior neurocognitive performance compared to those patients randomised to deferred ART </li></ul></ul><ul><li>Rationale </li></ul><ul><ul><li>Early ART will afford HIV viral suppression, higher CD4+ cell counts and improved peripheral immunity all of which are integral to the control of CNS HIV infection </li></ul></ul>
  48. 48. How are HIV-1 Associated Neurocognitive Disorders (HAND) now classified? <ul><li>ANSWER </li></ul><ul><li>Asymptomatic Neurocognitive Impairment (ANI) </li></ul><ul><ul><li>15% patients </li></ul></ul><ul><ul><li>Asymptomatic: only detectable with formal neuropsychological testing </li></ul></ul><ul><li>Mild Neurocognitive Disorder (MND) </li></ul><ul><ul><li>Up to 40% patients pre- & post-HAART </li></ul></ul><ul><ul><li>Causes mild-moderate impact on function at work and home </li></ul></ul><ul><li>HIV-Associated Dementia (HAD) </li></ul><ul><ul><li>Incidence 7% per year CD4+ cells < 200/uL pre-HAART and 3% per year post-HAART’ </li></ul></ul><ul><ul><li>Causes significant impact upon function at home and work </li></ul></ul><ul><ul><ul><li>Updated Research Nosology for HIV-associated Neurocognitive Disorders, </li></ul></ul></ul><ul><ul><ul><li>Antinori et al, Neurology 2007 </li></ul></ul></ul>
  49. 49. START Neurology Substudy <ul><li>Inclusion criteria </li></ul><ul><ul><li>Simultaneous co-enrollment in the START Study </li></ul></ul><ul><ul><li>Signed informed consent </li></ul></ul><ul><ul><li>Age ≥ 18 years </li></ul></ul><ul><li>Exclusion criterion </li></ul><ul><ul><li>Patient unable to perform necessary tests in protocol, in the clinician’s judgment </li></ul></ul>
  50. 50. Measures of Neurocognitive Functioning <ul><li>Quantitative QNPZ-8 score </li></ul><ul><ul><li>Color Trails 1 and 2 </li></ul></ul><ul><ul><li>Grooved Pegboard </li></ul></ul><ul><ul><li>Finger tapper </li></ul></ul><ul><ul><li>Hopkins Verbal Learning Test and Recall </li></ul></ul><ul><ul><li>WAIS-III Digit Symbol </li></ul></ul><ul><ul><li>Verbal Fluency </li></ul></ul><ul><li>Sensitive and relatively impervious to effects of culture, ethnicity and education </li></ul><ul><li>Relatively simple to teach and administer </li></ul><ul><li>Administration time  45 minutes </li></ul><ul><li>CES-D Screening for depression </li></ul><ul><li>Baseline, month 4, 8, 12, 24 </li></ul>Finger Tapper courtesy Prof Robertson; www.amazon.com
  51. 51. Study Endpoints <ul><li>Primary Endpoint </li></ul><ul><ul><li>Change in QNPZ-8 scores </li></ul></ul><ul><li>Secondary Endpoints </li></ul><ul><ul><li>Change in test scores for each of the eight neuropsychological tests </li></ul></ul><ul><ul><li>Change in average deficit score (ADS) </li></ul></ul><ul><ul><li>Proportion of participants with neurocognitive impairment </li></ul></ul>
  52. 52. Arterial Elasticity Substudy At 24 participating sites
  53. 53. START Arterial Elasticity Substudy <ul><li>Purpose : To determine if participants randomized to early ART will have increased large-artery and small-artery elasticity (LAE and SAE; i.e., reduced arterial stiffness) compared to those randomized to deferred ART </li></ul>Co-enrolled in START N=300 Early ART Group N=150 Deferred ART Group N=150
  54. 54. Atherosclerotic Risk and Disease: Surrogate Non-invasive Markers <ul><li>Structural Assessment </li></ul><ul><li>Carotid intima-media thickness (CIMT) </li></ul><ul><ul><li>Ultrasound </li></ul></ul><ul><li>Coronary calcification (CAC) </li></ul><ul><ul><li>Electron beam CT </li></ul></ul><ul><li>Arterial Stiffness/Elasticity </li></ul><ul><ul><li>Pulse velocity </li></ul></ul><ul><ul><li>Blood pressure waveform analysis </li></ul></ul><ul><li>Functional Assessment </li></ul><ul><li>Brachial artery flow-mediated dilation (FMD) </li></ul><ul><ul><li>Ultrasound pre/post-occlusion </li></ul></ul><ul><li>Arterial (leg) blood flow </li></ul><ul><ul><li>Intra-arterial vasodilator infusion </li></ul></ul><ul><li>Arterial Stiffness/Elasticity </li></ul><ul><ul><li>Pulse velocity </li></ul></ul><ul><ul><li>Blood pressure waveform analysis </li></ul></ul>Clinical Disease
  55. 55. Blood Pressure Waveform Analysis (via peripheral pulse)
  56. 56. CR-2000 System Components <ul><li>The Cardiovascular Profiling Instrument </li></ul><ul><li>Main Electrical Power Cord (Hospital Grade) </li></ul><ul><li>Printer Electrical Power Cord </li></ul><ul><li>Parallel Printer Data Cable </li></ul><ul><li>Ink-Jet Printer </li></ul><ul><li>Arterial PulseWave™ Sensor </li></ul><ul><li>Wrist Stabilizer </li></ul><ul><li>Blood Pressure Hose </li></ul><ul><li>Blood Pressure Cuffs (small, regular, large adult) </li></ul>
  57. 57. AE Substudy Visit Procedures: 1) BP waveform analysis <ul><li>Participant lying supine </li></ul><ul><li>Wrist stabilizer applied </li></ul><ul><li>Sensor placed over radial artery </li></ul><ul><li>BP cuff on contra-lateral arm </li></ul><ul><li>Research staff obtains optimal waveform tracing </li></ul><ul><li>Measurement recorded 3 times </li></ul><ul><li>BP recorded during each measure </li></ul><ul><li>Takes approximately 20-30 min. </li></ul>
  58. 58. Pulmonary Substudy At 91 participating sites
  59. 59. START Pulmonary Substudy HIV-infected patients with CD4+ counts >500 cells/mm 3 n = 1,000 (91 sites) Early ART group Initiate ART immediately following randomization n = 500 Deferred ART group Defer ART until CD4+ count declines to < 350 cells/mm 3 or AIDS develops n = 500 <ul><li>Spirometry </li></ul><ul><li>SGRQ-C </li></ul><ul><li>Respiratory medication assessment </li></ul><ul><li>Respiratory illness assessment </li></ul><ul><li>Smoking assessment </li></ul>HIV-infected patients with CD4+ counts >500 cells/mm 3 n = 4,000 Main Trial Pulmonary Substudy <ul><li>Main trial study procedures, </li></ul>At sites trained and certified to participate in pulmonary ancillary study: consent and enroll for ancillary study prior to randomization *Annual*
  60. 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”
  61. 61. Spirometry <ul><li>Simple setup, no calibration, portable </li></ul><ul><li>Disposable patient interface (no complex cleaning) </li></ul><ul><li>Training required, but relatively simple test </li></ul><ul><li>Same device used in other global studies of COPD epidemiology (see below) </li></ul>n = 5315 Spirometry done at participants ’ homes n = 9245 12 sites / countries
  62. 62. Summary <ul><li>HIV is an independent risk factor for COPD </li></ul><ul><li>The effect of ART on COPD risk / lung function is unknown </li></ul><ul><ul><li>Some studies suggest benefit </li></ul></ul><ul><ul><li>Some studies suggest harm </li></ul></ul><ul><li>START is likely to be the only opportunity to ever address this knowledge gap with a randomized trial </li></ul><ul><li>Enrollment progressing, but next 6 months will be critical </li></ul>
  63. 63. Bone Mineral Density Substudy At 43 participating sites
  64. 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
  65. 65. Low Bone Mineral Density (BMD) Osteopenia and Osteoporosis <ul><li>Bone mineral density is a measurement of the level of minerals in bones, an indication of density and strength </li></ul><ul><li>Osteopenia is a condition where bone mineral density is lower than normal peak BMD of a young adult, but not low enough to be considered osteoporosis </li></ul><ul><li>Osteopenia is considered to be a precursor to osteoporosis </li></ul><ul><li>BUT, not all osteopenia progresses to osteoporosis </li></ul>
  66. 66. Hypotheses <ul><li>Primary </li></ul><ul><ul><li>The early ART group will have more BMD loss than the deferred ART group. </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>Hip and spine BMD among untreated HIV-infected participants will decline at a constant rate, and risk factors for BMD loss will be similar to those for the general population. </li></ul></ul><ul><ul><li>Rates of BMD decline at hip and spine in the first year of ART will continue through follow-up. </li></ul></ul><ul><ul><li>BMD decline will be steeper among participants who receive tenofovir and/or a protease inhibitor (PI). </li></ul></ul>
  67. 67. Inclusion criteria <ul><li>Simultaneous co-enrollment in the START study. </li></ul><ul><li>Signed informed consent to the BMD substudy. </li></ul>
  68. 68. Exclusion criteria <ul><li>Inability to obtain valid BMD measurements from DXA scans, e.g., because of any of the following: </li></ul><ul><ul><li>weight >136 kg (300 lb) </li></ul></ul><ul><ul><li>height >1.98 m (6 ft 6 in) </li></ul></ul><ul><ul><li>implants in the measurement areas (spine L1-L4, or both hips) </li></ul></ul><ul><ul><li>surgery (such as laminectomy of the spine), severe degenerative changes of the spine, severe arthritis in both hips, or moderate to severe scoliosis </li></ul></ul><ul><li>Receiving osteoporosis drug treatment for low BMD </li></ul>
  69. 69. Malignancy Tissue Collection At all participating sites
  70. 70. START Malignancy Tissue Sample Collection <ul><li>Purpose : To collect a biopsy tissue and blood sample from participants who develop a malignancy during the course of the study for future research. </li></ul><ul><li>Design : part of main study data collection </li></ul><ul><li>Sample size : all START participants who consent to the additional specimen collection and develop a malignancy </li></ul>
  71. 71. <ul><li>For latest START accrual & other study info, check out the INSIGHT website: </li></ul><ul><li>www.insight-trials.org </li></ul><ul><li>HIV studies / START / Reports </li></ul>
  72. 73. Time to START <ul><li>START is a critically important randomized trial that will assess the benefits and risks of early treatment of HIV infection </li></ul><ul><li>For START to be a success, accrual must be rapid, follow-up complete, and protocol adherence high </li></ul><ul><li>Findings from START will impact treatment guidelines </li></ul><ul><li>Findings from START and its substudies will fuel new scientific research on the pathogenesis of HIV and other diseases </li></ul><ul><li>START now! </li></ul>

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