HIV i-Base: SMART Study & CROI Feedback UK-CAB - Feb 2006 UK-CAB 24 February 2006 CROI Feedback: SMART Study Simon Collins

HIV i-Base: SMART Study & CROI Feedback UK-CAB - Feb 2006

UK-CAB 24 February 2006

CROI Feedback: SMART StudySimon Collins


Background:

Do you need to be on continuous treatment? can you start and stop based on CD4 counts that are generally known to be safe or low risk?

Advantages: less drug use, less resistance (adherence), cost etcDisadvantages: risk, more infectious, more resistance (stopping), inflammatory responses


SMART: Study design

[Treatment interruptions]

Drug Conservation (DC)

[Stop or defer ART until CD4+ < 250; then episodic ART

based on CD4+ cell count to increase counts to > 350]

[Continuous Treatment]

Virologic Suppression (VS)

[Use of ART to maintain viral load as low as possible throughout follow-up]

CD4+ cell count >350 cells/mm3

n = 3000 n = 3000

Plan: 910 primary endpoints, 8 years average follow-up

Findings (11 Jan 06): 164 primary endpoints, 14 months average follow-up, 2% lost to follow-up


Primary Endpoint

•HIV clinical disease progression or death

Other Key Endpoints• Death• Serious HIV progression events• Severe complications: cardiovascular, renal and hepatic

Sub studies: bpdy shape, QoL etc


Baseline

Large, diverse study:Enrollment: 5473/6000 target

33 Countries, 318 Sites

57% US, 26% Europe, 10% L. America, 1% Africa

27% women, 30% Black, Age 46

Wide treatment experience:Baseline CD4 ~ 600; CD4 nadir ~250 cells/uL

70% <400 copies/mL; <5% patients were treatment naive

~25% prior AIDS

Median 6 year prior ARVs

~ 6000 pyfu ~2%LTFU


Baseline

Follow-up and enrollmentEnrollment started in US in Jan02

~150-250 pts enrolled every 3 months to Sep 2004 - all mainly US

So some pts followed for over 4 years

Last 3000 pts all enrolled Oct04-Dec05 - especially new countries

Wide baseline and nadir CD4 count:Baseline CD4 30% >750 cells/mm3

CD4 nadir - wide distribution: ~ 25% < 150 (inc, 10% <50 c/uL)

~ 10% 150-200 c/uL

~ 25% 200-300 c/uL etc


% Patients on ART at Each Month of Follow-up by Treatment Group

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36

Percent

Months from randomizationNumber of patients

VS Group

DC Group

% of Follow-Up Time on ART

VS arm: 93%

DC arm: 33%

Ie - A concern if these two lines become too close. At this distance, so long as it is maintain, ther trial remained ok for it’s main question

VS 2308 1167 628 335DC 2328 1188 613 337


HIV Disease Progression or Death

Logrank = 31.1 p < 0.0001

DC 2720 1170 589 322 34 VS 2752 1167 625 334 41

Months from randomization

DC Group

VS Group

Per

cen

t w

ith

Eve

nt

0 4 8 12 16 20 24 28 32 36 40 44

0

5

10

15

20


Primary EndpointClinical Disease Progression or Death

DC Group VS Group RR (DC/VS)

P-valueN Rate* N Rate* (95% CI)

117 3.7 47 1.5 2.5 (1.8, 3.6) <0.0001

* Per 100 person-yearsEl-Sadr W, et al. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 106LBEl-Sadr W, et al. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 106LB


0.1

1

10Relative Risk (95% CI)

Relative Risk of Primary Endpoint

by Follow-up Interval

0-1 1-2 2-3 3-4

Year of Follow-up

DC 56 37 15 9VS 19 11 11 6

No. Events

El-Sadr W, et al. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 106LBEl-Sadr W, et al. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 106LB


1.9

6.1

3.3

2.2

2.5

0.1 1 10

Primary Endpoint and Components

Favors VS ►►

Favors DC

No. of Patients

with EventsEndpoints

Relative Risk (95%

CI)Progression of Disease or Death 164

Death 84

Serious Progression 21

Non Serious Progression 72

Serious Progression of Disease or Death 101

>



2.3

2.0

2.5

3.6

3.4

0.1 1 10

HIV Progression or Death by Sex and Race

No. of Patients with Events

Subgroups

All Patients 164

Sex

Female 46

RaceBlack 71

Non Black 93

Favors VS ►

►

Favors DC

Relative Risk (95%

CI)

Male 118



0.1 1 10

Progression or Death By Baseline CD4

No. of Patients with Events

Subgroups

All Patients 164

Baseline CD4 (cells/mm3)350 - 449 44

450 - 549 36

550 - 649 24

≥ 650 60

Favors VS ►

►

Favors DC

Relative Risk (95%

CI)2.5

1.5

4.3

3.1

2.9



2.9

1.9

2.9

2.5

2.6

2.5

2.3

0.1 1 10

Progression of Disease or Death by Nadir CD4No. of

Patients with Events

Subgroups

All Patients 164

Nadir CD4 (cells/mm3)

100 – 199 35

200 – 299 39

300 – 399 40

≥ 400 22

50 – 99 10

Favors VS ►►

Favors DC

Relative Risk (95%

CI)

< 50 18



0.1 1 10

Progression or death by baseline viral loadNo. of

Patients with Events

Subgroups

HIV RNA (copies/ mL) - (pts on ART at baseline)

≤ 400 87

> 400 40

Favors VS ►

►

Favors DC

Relative Risk (95%

CI)

2.5

3.8

1.1

All Patients

This showed that the relative risk was almost 4x higher for people with undetectable viral load at baseline


Causes of DeathThere were 29 deaths in the continuous treatment arm vs 47 in DC arm.

The majority were related to non-AIDS events (ie approx 11 in each arm to heart disease, and similar number to violent/accident.)

Only ~5% were defined as ‘AIDS-related’

Cancer was related to ~15% of deaths in each arm

A larger number of ‘unknown’ reasons for death occurred in the DC arm (approx 20% vs 7%)

Investigators said that primary outcome of the analysis was not changed, even when ‘violent and unknown deaths were taken out of the analysis


0

5

10

15

20

25

30

35

< 200

< 250

< 350

Percent of Follow-up TimeBelow CD4+ Cell Count Thresholds

by Treatment Group

% o

f fo

llow

-up

time

VS GroupDC Group

31.7%

7.2%8.2%

1.7%3.1%0.8%



Summary• The DC strategy, compared to the VS strategy, is

associated with increased risk of:– HIV disease progression or death– Death– Serious HIV disease progression – Severe complications (cardiac, renal or hepatic)

• Risk of disease progression or death in DC versus VS group – Did not differ by nadir CD4+ cell count– Was three-fold higher for patients on ART with baseline HIV

RNA < 400 copies/ml compared to those on ART with baseline HIV RNA >400 copies/ml 3.2 [1.9,5.6] vs 1.1 [0.6,2.0]

• For other subgroups examined, risk was always greater in the DC group than the VS group


Conclusion

Episodic use of ART based on CD4+ cell count levels as per the SMART study design is inferior to continuous ART for the management of treatment-experienced patients. Thus, this strategy should not be recommended.


Discussion.1

Other research: SMART was one of six studies to get an oral presentation - all slides are online

• One study with similar CD4 criteria to restart at ~250 CD4 also stopped early

• Other studies, restarting at <350 CD4 didn’t find the same risk (ie Stacatto) - but this was a much smaller study

• In SMART was that ‘proximal’ CD4 count was not predictive of risk - death and serious events occurred at all CD4 counts including > 600 CD4 etc - though the lower the CD4 count the higher the relative risk.


Discussion.2

• Two arms appear to show differences after 4-6 months or treatment interruption. Median time off treatment was 18 months in SMART - question of whether shorter fixed periods off-treatment would narrow the difference compared to continuous treatment

• SMART designed when treatment was more difficult - dosing, pill count, tolerability now are improved for more patients now

• Some individuals still have great difficulty with HAART

• Always an individual choice - and data needed to inform this risk when balancing risk vs benefit


Discussion.3

• SMART provided clear answer to its study question

• Follow-up and further analysis are ongoing

• Quality of Life sub-study should be presented in Toronto in July 2006

• If SMART showed treatment to be ‘safer’ than anticipated when the study was first designed, does this reopen the ethics of a ‘when to start’ trial that randomises people to start at higher CD4 counts.


Additional slides


SMART1 Staccato2 Trivacan3

CD4 CountStartStop

250350

350350

250350

Disease progression per 100 patient years

STICT

3.71.5

0.20.4

17.66.7

Therapy Interruption: CD4 count guided

11 SMART: 13SMART: 13thth CROI 2006 Abstract 106LB CROI 2006 Abstract 106LB22 Staccato: 13Staccato: 13thth CROI 2006 Abstract 102 CROI 2006 Abstract 10233 Trivacan: 13Trivacan: 13thth CROI 2006 Abstract 105LB CROI 2006 Abstract 105LB

Documents

HIV i-Base: SMART Study & CROI Feedback UK-CAB - Feb 2006 UK-CAB 24 February 2006 CROI Feedback: SMART Study Simon Collins