1. Strategies for Management of Antiretroviral Therapy Study Wafaa El-Sadr and James Neaton for the SMART Study Team

2. 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

3. SMART Study Design Drug Conservation (DC) Strategy [Stop or defer ART until CD4+ 350] Virologic Suppression (VS) Strategy [Use of ART to maintain viral load as low as possible throughout follow-up] CD4+ cell count >350 cells/mm 3 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

4. Primary Endpoint HIV clinical disease progression or death Other Key Endpoints Death Serious HIV progression events Severe complications: cardiovascular, renal and hepatic

5. Baseline Characteristics - 1 57% 26% 10% 3% 1% Countries: 33 Sites: 318 Total enrollment: 5472 Age: 46 years Women: 27% Blacks: 30%

6. Baseline Characteristics – 2 DCVSTotal Median Baseline CD4+ (IQR)596599598 (466,792) Median Nadir CD4+ (IQR)250252251 (154,360) HIV RNA <400 c/mL (%)71.070.870.9 Prior Clinical AIDS (%)24.723.424.1 ART Naïve (%)4.54.84.7 Years of prior ART (IQR)666 (3,8)

7. Percent of Patients on ART at Each Month of Follow-up by Treatment Group Percent Months from randomization Number of patients VS Group DC Group Proportion of Follow-Up Time on ART VS arm: 93% DC arm: 33% VS23081167628335 DC23281188613337

8. Percent of Follow-up Time Below CD4+ Cell Count Thresholds by Treatment Group % of follow-up time VS GroupDC Group 31.7% 7.2% 8.2% 1.7% 3.1% 0.8%

9. Primary Endpoint Clinical Disease Progression or Death DC GroupVS Group RR (DC/VS) P-value N Rate* (95% CI) 117 3.7 47 1.5 2.5 (1.8, 3.6) <0.0001 * Per 100 person-years

10. HIV Disease Progression or Death Logrank = 31.1 p < 0.0001 DC 2720 1170 589322 VS 27521167625334 Months from randomization DC Group VS Group Percent with Event 048121620242832364044 0 5 10 15 20

11. Relative Risk (95% CI) Relative Risk of Primary Endpoint by Follow-up Interval 0-11-22-33-4 Year of Follow-up DC5637159 VS1911116 No. Events

12. Primary Endpoint and Components Favors VS ► ► Favors DC No. of Patients with Events Endpoints Relative Risk (95% CI) Progression of Disease or Death164 Death84 Serious Progression 21 Non Serious Progression 72 Serious Progression of Disease or Death101 >

13. Severe Complications Endpoint and Components No. of Patients with Events Subgroups Severe Complications114 Non-Fatal CVD Events63 Non-Fatal Hepatic Events14 Non-Fatal Renal Events7 Favors VS ► ► Favors DC Relative Risk (95% CI) 1.5 1.4 2.5 1.4 CVD, Liver, or Renal Deaths31 >

14. HIV Progression of Disease or Death by Sex and Race No. of Patients with Events Subgroups All Patients164 Sex Female46 Race Black71 Non Black93 Favors VS ► ► Favors DC Relative Risk (95% CI) Male118

15. Progression of Disease or Death By Baseline CD4+ Cell Count No. of Patients with Events Subgroups All Patients164 Baseline CD4 (cells/mm 3 ) 350 - 44944 450 - 54936 550 - 64924 ≥ 65060 Favors VS ► ► Favors DC Relative Risk (95% CI) 2.5 1.5 4.3 3.1 2.9

16. Progression of Disease or Death By Nadir CD4+ Cell Count No. of Patients with Events Subgroups All Patients164 Nadir CD4 (cells/mm 3 ) 100 – 19935 200 – 29939 300 – 39940 ≥ 40022 50 – 9910 Favors VS ► ► Favors DC Relative Risk (95% CI) < 5018

17. Progression of Disease or Death By Baseline HIV RNA in Patients Taking ART No. of Patients with Events Subgroups HIV RNA (copies/ mL) (patients on ART at baseline) ≤ 40087 > 40040 Favors VS ► ► Favors DC Relative Risk (95% CI) 2.5 3.8 1.1 All Patients

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

19. 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.

20. 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