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Strategic Timing of Antiretroviral Treatment
Community SlidesINSIGHT Washington ICC
August 2011
START
Strategic Timing of Antiretroviral Treatment
STUDY RATIONALE
START
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.
START
0.1 1 10
SMART: Severe Complications Endpoint and Components
No. of Patients with EventsSubgroups
Severe Complications 114
Non-Fatal CVD Events 63
Non-Fatal Hepatic Events 14
Non-Fatal Renal Events 7
Favors VS ►
►
Favors DC
Relative Risk (95% CI)
1.5
1.5
1.4
2.5
1.4CVD, Liver, or Renal Deaths 31
>
Selected Publications on Non-AIDS Events
Evolution of Focus of Concern
Opportunisticinfections &malignancies
CMVPCPMAC
ToxoplasmosisCryptococcosis
CandidiasisHistoplasmosisKaposi Sarcoma
Complications of therapy
CVDMetabolic
Renal Hepatic
NeurologicHematologic
Serious,non-AIDS
morbidities
MIStroke
Renal FailureHepatic FailureMalignancies
Time
A New Paradigm:
Time in YearsInfection
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
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
<200
CD4 1996
1998
2000
2002
2004
2006
2008
2010
CD4 <350
CD4 350-500
CD4 >500
EACS, 2009
treat deferW/ SPECIAL
CONSIDERATIONS
defer
US DHHS, 2011
treat treat No consensus
WHO 2010 treat --- ---
When to start ART?Summary of Current Guidelines
For asymptomatic patients
2011 US Guidelines
“Randomized controlled trials provide evidence supporting the benefit of antiretroviral therapy in patients with CD4 counts of 350 cells/mm3 or less. However, such evidence showing benefit for patients with higher CD4 cell counts is not yet available…”
Evidence from Randomized Trials for Initiating Treatment at CD4 200-350
• CIPRA-HT001 – a single center trial in Haiti
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/mm3 (IQR: 130, 190).
• A post-hoc analysis of the SMART Study
Only involved 477 patients and of these only 249 were ART-naïve.
• HPTN 052 Deferral strategy was 200-250 cells; significant difference in extrapulmonary TB; not powered to address survival (10 versus 13 deaths).
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)
SMART subset analyses
A subset of SMART participants not on ART at baseline were examined; this analysis further informed the design of START
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 GroupHR (DC/VS)
Deferred vs. EarlyP-valueN Rate N Rate 95% CI
• OD or death 15 4.8 4 1.1 4.4 [1.5, 13.2] 0.009
• OD fatal or non-fatal 11 3.5 3 0.8 4.4 [1.2, 15.8] 0.02
• Serious non-AIDS 12 3.9 2 0.5 7.1 [1.6, 31.5] 0.01 • Composite 21* 7.0 5 1.3 5.1 [1.9, 13.5] 0.001
Emery et al, JID, April 2008
Evidence from Observational Studies for Initiating ART with CD4 > 350
Comparison CD4+ count strata HR for death
NA ACCORD <350 vs 350-500 1.7 (1.3 - 2.3)
350-500 vs > 500 1.9 (1.4 – 2.8)
ART CC 251-350 vs 351-450 1.1 (0.8 - 1.6)
351-450 vs 451-550 0.9 (0.6 - 1.4)
HIV-Causal 350 vs 500 1.0 (0.8-1.2)
• Kitahata MM et al, N Engl J Med 2009 • When to Start Consortium, Lancet 2009• HIV Causal Collaboration, Annals Int Med, 2011
Evidence from HPTN 052:ART prevents HIV transmission
• 1763 discordant couples (one HIV-infected partner)• Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand,
Zimbabwe (+ single US couple)• CD4 count at entry: 350 – 550 cells/mm₃
• Index case randomized to IMMEDIATE ART vs DEFERRED ART• Deferral until CD4 count drops to < 250 cells/mm₃ or disease
RESULTS:
• 1 new HIV infection in partners of those on ART• 27 new HIV infections in partners of those deferring ART• 96% efficacy of ART to prevent transmission in this population
Evidence Needed to Guide Decisions on Individual Patient Management
• Benefit of early HIV treatment on serious clinical events (AIDS & non-AIDS)
• Effect of early HIV treatment on:– Metabolic abnormalities– Body composition– Adverse events– Resistance – Adherence & regimen use– Cost
Strategic Timing of Antiretroviral Treatment
PROTOCOL OVERVIEW
START
START Design
HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3
Early ART Group
Initiate ART immediately following randomization
N=2,000
Deferred ART Group
Defer ART until the CD4+ count declines to < 350 cells/mm3 or
AIDS develops
N=2,000
Inclusion Criteria
• Signed informed consent• Documentation of HIV infection• Age ≥ 18 years• Karnofsky performance score ≥ 80• Perceived life expectancy of at least 6 months• For women of childbearing potential, willingness to use
contraceptives as described in the product information of the ART drugs they are prescribed
• Two CD4+ cell counts > 500 cells/mm3 at least 2 weeks apart
Exclusion Criteria• Any previous ART or IL-2• Diagnosis of any clinical AIDS event• Presence of HIV progression such as oral thrush, unexplained weight
loss, or unexplained fever• Within 6 months prior to randomization, any of the following:
o Cardiovascular event (MI, angioplasty, CABG, stroke)
o Non-AIDS-defining cancer (excluding basal and squamous cell skin cancer)
o Dialysis• History of decompensated liver disease• Current imprisonment or compulsory detention (involuntary incarceration)
for treatment of a psychiatric or physical illness• Current pregnancy or breastfeeding
Primary Study Endpoint(Time to first event)
• AIDS* or death from AIDSOpportunistic 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.
• Non-AIDSo Cardiovascular disease (CVD) (MI, angioplasty, CABG, stroke)o Chronic end-stage renal disease (ESRD) (initiation of dialysis, renal transplantation)o Decompensated liver diseaseo Non-AIDS defining cancers (basal and squamous cell skin cancers are not counted)
• Death not attributable to AIDS, including death of unknown cause
Secondary Endpoints (1)
• Individual components of composite primary endpoint• Bacterial pneumonia• Adverse events• Hospitalization• Quality of life• Health care utilization and cost of care• HIV transmission risk behavior• HIV drug resistance
Secondary Endpoints (2)
• Pulmonary embolism or deep vein thrombosis• New-onset diabetes mellitus• Coronary artery disease requiring drug treatment• Congestive heart failure• Peripheral arterial disease• Change in estimated GFR and development of proteinuria• Blood pressure and blood lipids• ECG abnormalities• Use of BP- or lipid-lowering treatment or aspirin
Sample Size for Definitive Study• 90% power and alpha = 0.05 (2-sided) N = 4,000 • Hypothesized risk reductions with early ART (compared to no ART) are:
– AIDS* = 43%– Serious non-AIDS = 24% – Composite of AIDS* (20% of events) and non-AIDS (80% of events)
= 28.8%• Rate in deferred ART group for composite outcome = 2.8 per 100 person
years• 4.5 years average follow-up• Loss to follow-up rate of 2.7 per 100 person years, equivalent to 15%
cumulative lost to follow-up after 6 years• Hypothesized hazard ratio after considering use of ART in the deferred
arm and non-adherence in early ART arm = 0.71• 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
A Two-Phased Approach for START
• Pilot Phase to Assess Feasibility: Completed– Establish that the trial can be enrolled– Demonstrate excellent follow-up and protocol adherence
• Definitive Trial: N = 4,000 (est.) Ongoing– Enroll additional participants – Estimate event rate in the deferred arm and the fraction of
events that are non-AIDS– Re-estimate sample size in mid-2012– Follow all participants, including those enrolled in pilot
phase, for 3 – 5 more years (est. December 2015)
START Collaboration with Pharma
Abbott: Ritonavir, Lopinavir/Ritonavir (tablets for both in 2012)
Bristol-Myers Squibb: Efavirenz, Atazanavir, Atripla®
Gilead: Truvada, Atripla®
GlaxoSmithKline: Fosamprenavir, Combivir®, Epzicom®
Merck: Efavirenz, Raltegravir (available mid-2011)
Tibotec: Darunavir
ART in START
• ART must be from one of two sources:
-- INSIGHT repository
-- FDA-approved or tentatively approved drugs available locally (eg. from Global Fund sources)
• Initial ART Regimen prescribed must be from INSIGHT Web Table
• Clinicians may choose subsequent regimens from among all available approved drugs
Initial ART Regimens in STARTTo 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
As of 14 January 2010
START STUDY Funding• Division of AIDS, The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) PRIMARY FUNDER
Other NIH support: -Department of Bioethics, The Clinical Center -Division of Clinical Research (NIAID) -National Cancer Institute (NCI) -National Heart, Lung, and Blood Institute (NHLBI) -National Institute of Child Health and Human Development (NICHD) -National Institute of Mental Health (NIMH) -National Institute of Neurological Disorders and Stroke (NINDS) -National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS)• Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS, France)• Bundesministerium für Bildung und Forschung (BMBF, Germany)• NEAT - European AIDS Treatment Network• Australian National Health and Medical Research Council (NHMRC)• National Institute for Health Research, UK• Medical Research Council, UK• University of Minnesota
START Study Definitive Phase4 ICCs – 36 Countries – 240 Sites
WashingtonICC
SydneyICC
CopenhagenICC
LondonICC
BrazilMaliPeruSouth AfricaUnited States
ArgentinaAustraliaChileIndiaIsraelMalaysiaMexicoNigeriaSingaporeThailand
AustriaBelgiumCzech Rep.DenmarkEstoniaFinlandGermanyLuxembourgNorwayPolandPortugalSpainSweden
FranceGreeceIrelandItalyMoroccoSwitzerlandUgandaUnited Kingdom
Strategic Timing of Antiretroviral Treatment
A Multicenter Study by INSIGHT –International Network for Strategic Initiatives
in Global HIV Research
START SUBSTUDIES
START
START Substudies• Genomics (NIAID, NCI)
• Informed Consent (NIH Clinical Bioethics Dept.)
• Neurology (NIMH, NINDS)
• Arterial Elasticity (NHLBI)
• Pulmonary Function (NHLBI)
• Bone Mineral Density (NIAMS)
• Malignancy Tissue Collection (NCI)
START Substudies
• A means to maximize scientific gain from the effort
• Funding from a variety of sources
• An opportunity for a broader group of investigators to become involved
• Some substudies open at all sites – some at selected sites – based in part on sample size
• Each site needs to balance appeal of substudy to staff and patients with workload issues
• Additional substudies may be added
37
Genomics Substudy
START
Open to all participating sites
START38
Study Purpose
“…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.”
START39
Study Design
• Nonrandomized multicenter study• Maximum of all START participants • Open to all sites • Inclusion criteria
– Consent to randomization in START – Signed informed consent for the substudy
• Exclusion criteria– None
40
Informed Consent Substudy
START
Open to all participating sites
41
START Informed Consent Substudy
Purpose
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.
42
Informed Consent Substudy Background
• Consent forms for clinical trials are often long, technical, and legalistic.
• Data show that research participants have limited understanding of study information
• 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
43
Informed Consent Substudy Hypothesis
• 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.
• Satisfaction with the process will be higher for the concise group.
44
Informed Consent Substudy Consent Forms
• 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 *
• Both consent forms tell participants that they are participating in this substudy, and that they will only get one of the forms
* CFR = United States Code of Federal Regulations
45
Neurology Substudy
START
At 36 participating sites
START46
START Neurology Substudy
HIV-infected, ARV naïve, CD4+ cell counts > 500 cells/mm3
Co-enrolled in START Study N=600
Early ART GroupN=300
Immediately initiate ART
Deferred ART GroupN=300
Defer ART until CD4+ <350 cells/mm3 or symptoms
develop
START47
START Neurology Substudy
• Hypothesis– Patients randomised to early ART will have
superior neurocognitive performance compared to those patients randomised to deferred ART
• Rationale– 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
START48
How are HIV-1 Associated Neurocognitive Disorders (HAND) now classified?
ANSWER1. Asymptomatic Neurocognitive Impairment (ANI)
• 15% patients• Asymptomatic: only detectable with formal neuropsychological
testing
2. Mild Neurocognitive Disorder (MND)• Up to 40% patients pre- & post-HAART• Causes mild-moderate impact on function at work and home
3. HIV-Associated Dementia (HAD)• Incidence 7% per year CD4+ cells < 200/uL pre-HAART and 3%
per year post-HAART’• Causes significant impact upon function at home and work
Updated Research Nosology for HIV-associated Neurocognitive Disorders,
Antinori et al, Neurology 2007
START49
START Neurology Substudy
• Inclusion criteria– Simultaneous co-enrollment in the START
Study– Signed informed consent– Age ≥ 18 years
• Exclusion criterion– Patient unable to perform necessary tests in
protocol, in the clinician’s judgment
START50
Measures of Neurocognitive Functioning
• Quantitative QNPZ-8 score– Color Trails 1 and 2 – Grooved Pegboard– Finger tapper– Hopkins Verbal Learning Test
and Recall– WAIS-III Digit Symbol– Verbal Fluency
• Sensitive and relatively impervious to effects of culture, ethnicity and education
• Relatively simple to teach and administer
• Administration time 45 minutes• CES-D Screening for depression• Baseline, month 4, 8, 12, 24
Finger Tapper courtesy Prof Robertson; www.amazon.com
START51
Study Endpoints
• Primary Endpoint– Change in QNPZ-8 scores
• Secondary Endpoints– Change in test scores for each of the eight
neuropsychological tests – Change in average deficit score (ADS)– Proportion of participants with neurocognitive
impairment
52
Arterial Elasticity Substudy
START
At 24 participating sites
START Arterial Elasticity Substudy
• 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
Co-enrolled in START N=300
Early ART GroupN=150
Deferred ART GroupN=150
Atherosclerotic Risk and Disease: Surrogate Non-invasive Markers Atherosclerotic Risk and Disease: Surrogate Non-invasive Markers
Structural Assessment
• Carotid intima-media thickness (CIMT)– Ultrasound
• Coronary calcification (CAC)– Electron beam CT
• Arterial Stiffness/Elasticity– Pulse velocity– Blood pressure waveform analysis
Functional Assessment
• Brachial artery flow-mediated dilation (FMD)– Ultrasound pre/post-occlusion
• Arterial (leg) blood flow– Intra-arterial vasodilator infusion
• Arterial Stiffness/Elasticity– Pulse velocity– Blood pressure waveform analysis
Clinical DiseaseClinical Disease
Blood Pressure Waveform Analysis(via peripheral pulse)
CR-2000 System ComponentsA. The Cardiovascular Profiling
Instrument
B. Main Electrical Power Cord (Hospital Grade)
C. Printer Electrical Power Cord
D. Parallel Printer Data Cable
E. Ink-Jet Printer
F. Arterial PulseWave™ Sensor
G. Wrist Stabilizer
H. Blood Pressure Hose
I. Blood Pressure Cuffs (small, regular, large adult)
AE Substudy Visit Procedures: 1) BP waveform analysis
• Participant lying supine
• Wrist stabilizer applied
• Sensor placed over radial artery
• BP cuff on contra-lateral arm
• Research staff obtains optimal waveform tracing
• Measurement recorded 3 times
• BP recorded during each measure
• Takes approximately 20-30 min.
58
Pulmonary Substudy
START
At 91 participating sites
START
START Pulmonary Substudy
HIV-infected patients with CD4+ counts >500 cells/mm3
n = 1,000 (91 sites)
Early ART groupInitiate ART immediately following randomization
n = 500
Deferred ART groupDefer ART until CD4+ count
declines to < 350 cells/mm3 or AIDS develops
n = 500•Spirometry•SGRQ-C
•Respiratory medication assessment
•Respiratory illness assessment•Smoking assessment
HIV-infected patients with CD4+ counts >500 cells/mm3
n = 4,000 Main TrialMain Trial
Pulmonary SubstudyPulmonary Substudy
•Main trial study procedures,
At sites trained and certified to participate in pulmonary ancillary study: consent and enroll for ancillary study prior to randomization
*Annual*
START
HIV and COPD
Hypothesis: In patients with HIV infection (ART-naïve and with CD4>500), immediate ART slows the rate of FEV1 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 (FEV1) over a 3 to 5 year follow-up period, separately for smokers and non-smokers.
Unknown: Does ART change the rate of FEV1 decline in patients with HIV infection?
“Disease Modification”
START
Spirometry• Simple setup, no calibration, portable• Disposable patient interface (no complex cleaning)• Training required, but relatively simple test• Same device used in other global studies of
COPD epidemiology (see below)
n = 5315n = 5315Spirometry Spirometry done at done at participantsparticipants’’ homeshomes
n = 9245n = 924512 sites / 12 sites / countriescountries
START
Summary• HIV is an independent risk factor for COPD• The effect of ART on COPD risk / lung function is
unknown– Some studies suggest benefit– Some studies suggest harm
• START is likely to be the only opportunity to ever address this knowledge gap with a randomized trial
• Enrollment progressing, but next 6 months will be critical
63
Bone Mineral Density Substudy
START
At 43 participating sites
64
Bone Mineral Density Substudy
HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3
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/mm3 or
AIDS develops
N=200
Low Bone Mineral Density (BMD)Osteopenia and Osteoporosis
• Bone mineral density is a measurement of the level of minerals in bones, an indication of density and strength
• 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
• Osteopenia is considered to be a precursor to osteoporosis
• BUT, not all osteopenia progresses to osteoporosis
Hypotheses
• Primary– The early ART group will have more BMD loss than
the deferred ART group.
• Secondary– 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.
– Rates of BMD decline at hip and spine in the first year of ART will continue through follow-up.
– BMD decline will be steeper among participants who receive tenofovir and/or a protease inhibitor (PI).
66
Inclusion criteria
• Simultaneous co-enrollment in the START study.
• Signed informed consent to the BMD substudy.
67
Exclusion criteria• Inability to obtain valid BMD measurements from
DXA scans, e.g., because of any of the following:– weight >136 kg (300 lb)
– height >1.98 m (6 ft 6 in)
– implants in the measurement areas (spine L1-L4, or both hips)
– surgery (such as laminectomy of the spine), severe degenerative changes of the spine, severe arthritis in both hips, or moderate to severe scoliosis
• Receiving osteoporosis drug treatment for low BMD
68
69
Malignancy Tissue Collection
START
At all participating sites
START Malignancy Tissue Sample Collection
• Purpose: To collect a biopsy tissue and blood sample from participants who develop a malignancy during the course of the study for future research.
• Design: part of main study data collection
• Sample size: all START participants who consent to the additional specimen collection and develop a malignancy
For latest START accrual & other study info, check out the INSIGHT website:
www.insight-trials.org
HIV studies / START / Reports
Time to START• START is a critically important randomized trial that will
assess the benefits and risks of early treatment of HIV infection
• For START to be a success, accrual must be rapid, follow-up complete, and protocol adherence high
• Findings from START will impact treatment guidelines
• Findings from START and its substudies will fuel new scientific research on the pathogenesis of HIV and other diseases
• START now!