Strategies for Management of Antiretroviral Therapy Study

Wafaa El-Sadr and James Neaton for the SMART Study Team

Background and Rationale

• Antiretroviral therapy (ART) is associated with marked reduction in morbidity and mortality

• Continuous use of ART can be associated with:– Waning adherence– Accumulation of resistance mutations– Serious cardiovascular and metabolic complications– Drug Costs

• Strategies are needed that optimize the use of ART: maximizing benefits, minimizing risks

SMART Study Design

Drug Conservation (DC) Strategy

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

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

Virologic Suppression (VS) Strategy

[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

Baseline Characteristics - 1

North AmericaEuropeSouth AmericaAustralia/NZAsiaAfrica

57%

26%

10%3% 3% 1% Countries: 33

Sites: 318

Total enrollment: 5472

Age: 46 yearsWomen: 27%Blacks: 30%

Baseline Characteristics – 2DC VS Total

Median Baseline CD4+ (IQR) 596 599 598 (466,792)

Median Nadir CD4+ (IQR) 250 252 251 (154,360)

HIV RNA <400 c/mL (%) 71.0 70.8 70.9

Prior Clinical AIDS (%) 24.7 23.4 24.1

ART Naïve (%) 4.5 4.8 4.7

Years of prior ART (IQR) 6 6 6 (3,8)

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

0102030405060708090

100

0 12 24 36

Percent

Months from randomizationNumber of patients

VS Group

DC Group

Proportion of Follow-Up

Time on ART

VS arm: 93%

DC arm: 33%

VS 2308 1167 628 335DC 2328 1188 613 337

0

5

10

15

20

25

30

35

< 200< 250< 350

Percent of Follow-up TimeBelow CD4+ Cell Count Thresholds

by Treatment Group%

of f

ollo

w-u

p tim

e

VS GroupDC Group

31.7%

7.2%8.2%

1.7%3.1% 0.8%

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-years

HIV Disease Progression or Death

Logrank = 31.1 p < 0.0001

DC 2720 1170 589 322 VS 2752 1167 625 334

Months from randomization

DC Group

VS Group

Perc

ent w

ith E

vent

0 4 8 12 16 20 24 28 32 36 40 440

5

10

15

20

0.1

1

10R

elat

ive

Ris

k (9

5% C

I)

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 9

VS 19 11 11 6No. Events

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

>

0.1 1 10

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

>

2.3

2.0

2.5

3.6

3.4

0.1 1 10

HIV Progression of Disease or Death

by Sex and RaceNo. of Patients

with EventsSubgroups

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 of Disease or Death By Baseline CD4+ Cell Count

No. of Patients with EventsSubgroups

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 CD4+ Cell Count

No. of Patients with EventsSubgroups

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 of Disease or Death By Baseline HIV RNA in Patients Taking ART

No. of Patients with EventsSubgroups

HIV RNA (copies/ mL)(patients on ART at baseline)

≤ 400 87

> 400 40

Favors VS ►

►

Favors DC

Relative Risk (95% CI)

2.5

3.8

1.1

All Patients

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

• 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.

Acknowledgements

Support provided by Division of AIDS, NIAID, NIH

The study is carried out by the Community Programs for Clinical Research on AIDS (CPCRA) in collaboration with Regional Coordinating Centers in Copenhagen, London and Sydney

Thanks to many thousands of patients and hundreds of investigators