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Transcript of Start impaact june 7 2011
Strategic Timing of Antiretroviral Treatment
Washington International Coordinating Center (DC ICC)IMPAACT Site Training
7 June 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
Natural History of Untreated HIV-1 Infection Revisited
Time in YearsInfection
CD4Cells
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
Clinical Latency
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
Time in YearsInfection
CD4Cells
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
Can Anything be Done?
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
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 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)• Brazil, India, Malawi, 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 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
Why Early Treatment Should be Studied NOW
• Compelling evidence of morbidity in early HIV disease
• Increasing numbers of individuals aware of HIV status
• Urgent need for definitive evidence to guide individual patient care and to inform guidelines
• This evidence will have profound global public health impact
• Findings from START and its substudies will fuel new scientific research on the pathogenesis of HIV and other diseases
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
START Substudies
• Genomics (NIAID, NCI)
• Informed Consent (NIH Clinical Bioethics Dept.)
• Neurology (NIMH, NINDS)
• Arterial Elasticity (NHLBI)
• Pulmonary Function (NHLBI)
• Bone Mineral Density (NIAMS)
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
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
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– 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
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
Strategic Timing of Antiretroviral Treatment
STUDY FUNDING & ORGANIZATION
START
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)• UK National Institute for Health Research
START Sponsor
• The University of Minnesota is the START sponsor– US Government agencies are restricted from
fulfilling some sponsor requirements in Europe– New paradigm for sponsorship of NIH-funded
trials– University has a financial interest in abacavir
(royalty income)
Who is Responsible for START ?
• Study Sponsor – University of Minnesota• INSIGHT Network Leadership and Protocol Team• INSIGHT Statistical and Data Management
Center (SDMC) and Core Operations Center (MNCC)
• International Coordinating Centers (ICCs)• Site Coordinating Centers (SCCs)• Site Investigators
START Study Definitive Phase4 ICCs – 36 Countries – 237 Sites
WashingtonICC
SydneyICC
CopenhagenICC
LondonICC
BrazilMaliPeruSouth AfricaUnited States
ArgentinaAustraliaChileIndiaIsraelMalaysiaMexicoNigeriaSingaporeSouth AfricaThailand
AustriaBelgiumCzech Rep.DenmarkEstoniaFinlandGermanyLuxembourgNorwayPolandPortugalSpainSweden
FranceGreeceIrelandItalyMoroccoSwitzerlandUgandaUnited Kingdom
Washington ICC Responsibilities
• Interface between INSIGHT SDMC and Clinical Research Sites
• Protocol Implementation– Education and Training– Data Quality Management– Resolution of Data Queries and Monitoring issues– Feedback to INSIGHT on protocols and CRFs
Washington ICC Responsibilities
• Regulatory compliance• Clinical Site Monitoring• Contractual and Fiscal Management• Coordination of Community Constituency
Group (CCG)
Research Management Team -1
Elizabeth Finley
Barbara Standridge
Research Managers
• Protocol management• Protocol-related questions• Query resolution• Regulatory questions or problems• Lab issues• Pharmacy issues• Data Quality Management• Training and education• Monitoring follow-up
Research Management Team -2
Adriana Sanchez
Research Management Associates
• Regulatory submissions – FWA, continuing review, protocol registration and deregistration, site establishment, IOR, 1572
• Staff and site changes• Supply shipping• Label orders
Shirley Cummins
Research Management Team -3
Doug Thomas
Part-time Research Managers
• Review and distribute monitoring Action Item Summaries
• Assist with Data Quality Management
Laura Lynch
Community Constituency Group
Melissa Turner
CCG Manager
• Coordinates CCG Activities• Liaison: CCG to Washington ICC• Coordinates with CAB Liaisons• Education and Training• Information Dissemination
Project Administrator
Michael Vjecha, MD
• Coordinates INSIGHT science• Coordinates Central Drug Repository• ICC Medical Officer for Serious Events
reported in START• Manages Contracts and Task Orders• Manages Invoices and Payments
DC ICC Communications
• START Site Leaders Calls – Quarterly and as needed
• START Site Coordinator Calls– Monthly
DC ICC Contact Information
• Research Managers – E-mail: [email protected]– Phone: 202-518-4609– Fax: 202-518-4610
• Dr. Michael Vjecha– E-mail: [email protected]– Phone: 202-745-8000, ext. 7930
Strategic Timing of Antiretroviral Treatment
ACCRUAL &BASELINE CHARACTERISTICS
START
START: Where are we now?ICC Sites Sites Registered Sites open N
Participants
Copenhagen 58 33 29 399
London 49 27 24 239
Sydney 48 22 17 224
Washington 80 43 39 445
Total 236 125 109 1307
As of 31 May 2011
53
Enrollment by Month 31 May
CDR opens
Enrollment by CountryCountry N (%) Country N (%)
USA 192 (15) Australia 45 (4)
Germany 185 (15) Poland 39 (3)
Brazil 96 (7) Chile 39 (3)
Spain 81 (6) Greece 27 (2)
France 77 (6) Mali 24 (2)
UK 77 (6) Denmark 23 (2)
Argentina 70 (5) Morocco 22 (2)
South Africa 61 (5) Switzerland 18 (1)
Thailand 59 (5) Finland 15 (1)
Belgium 54 (4) Italy 11 (1)
Peru 54 (4) Israel 10 (1)
Demographics Median Age (years, IQR) 36 [29, 44]
Gender (% female) 16
Race (%)
Asian 6
Black 17
Latino/Hispanic 14
White 61
Other 2
Age Distribution
28
3229
12
0
5
10
15
20
25
30
35
18-29 30-39 40-49 50+
Pe
rce
nt
Age Group
START Baseline CD4 Distribution
3634
15
86
0
5
10
15
20
25
30
35
40
501-600 601-700 701-800 801-900 >900
Pe
rce
nt
(%)
CD4 Cell Count (cells/mm3)
Median (IQR) 634 (577 - 720)
Sample size assumptions:
501-600 70%601-700 20% > 700 10%
Baseline CD4 Distribution
3733
16
86
0
5
10
15
20
25
30
35
40
500-599 600-699 700-799 800-899 900+
Pe
rce
nt
(%)
CD4 Cell Count (cells/mm3)
Median (IQR) 634 (576 - 726)
Baseline HIV-RNA Distribution
6
37
48
9
0
10
20
30
40
50
60
0-400 401-10K 10K-100K 100K+
Pe
rce
nt
(%)
HIV-RNA Level (copies/mL)
Median (IQR) 14,090 (3,789 – 43,889)
Percent with Clinically Elevated Modifiable CVD Risk Factors, by Region
40
47
37
27
21
41
16
8
2
13
58
31
22
1014
2220
7
2 1 15
3
0
5
10
15
20
25
30
35
40
45
50
US Europe SouthAmerica
Australasia Africa Overall
Current Smoker Cholesterol >= 240 mg/dL or on Rx
Hypertension (Stage 1 or 2 or on Rx) Diabetes (Diagnosis or on Rx)
Per
cen
t (%
)
% of Participants With Favorable* CVD Risk Factor Profile
Age (years)
< 30 31-40 41-50 > 50
Men 25% 16% 9% 12%(N=245) (N=278) (N=237) (N=82)
Women 36% 33% 10% 8%(N=53) (N=43) (N=41) (N=26)
cholesterol < 200 mg/dL SBP < 120 DBP < 80
non-smokerno diabetesno prior CVD
*
Follow-up Completeness
Visit No. Expected
Percent
Completed
Month 1 1148 97
Month 4 960 97
Month 8 634 94
Month 12 265 93
Month 16 91 94
Month 20 37 100
Month 24 5 100
Overall 3140 96
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: the time is now