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