Start study slides_dc_icc_ccg_11-aug-11

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

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Genomics Substudy

START

Open to all participating sites

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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

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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

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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.

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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

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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

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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.

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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

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Bone Mineral Density Substudy

START

At 43 participating sites

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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).

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Inclusion criteria

• Simultaneous co-enrollment in the START study.

• Signed informed consent to the BMD substudy.

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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

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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!