Calvin Cohen Research Director, Community Research Initiative of New England, Boston, MA, USA

1. Achieving your goals Invirase 500: the preferred partner in double boosting Calvin CohenResearch Director, Community Research Initiative of New England, Boston, MA, USA Research Director,Harvard Vanguard Medical Associates,Boston, MA, USA

2. Invirase/r case study:Tommy

3. Tommy: background information • 45 year old African American male • Full time job driving a taxi in Boston • Lives with girlfriend • Tested positive mid-1996 prompted by routine testing suggested in clinic • Heterosexually acquired HIV – year of exposure unknown • Borderline hypertension • Smokes 10 cigarettes per day • Cholesterol 147 mg/dl, HDL 52 mg/dl

4. Starting treatmentin the dual NRTI era • Baseline viral load: 42,656 copies/ml • Baseline CD4 count: 265, repeat 300 cells/mm3 • Wants to start on treatment Jan 1997: starts on stavudine and lamivudine • Wants to avoid ZDV, PI data just emerging • Good initial response: • Viral load: decreases to 500–1500 copies/ml • CD4 count: increases to 734 cells/mm3 • Ten pound weight gain noted, mild lipoatrophy

5. Unsuccessful switch to NNRTI regimen Jan 2000, viral load rebound and CD4 decrease Mar 2000: switches to: • Efavirenz, didanosine and abacavir • Nadir viral load: 4,000 copies/ml • Remains on regimen given initial CD4 stability • Over one year, CD4 count stable

6. Treatment response Jan 1997 to Mar 2001 d4T+3TC EFV+ddI+ABC 800 100,000 700 600 10,000 500 CD4 count (cells/mm3) HIV RNA (log10 copies/ml) 400 1,000 300 100 200 100 0 10 Jul-04 Jul-97 Jul-98 Jul-99 Jul-00 Jul-01 Jul-02 Jul-03 Jan-05 Jan-97 Jan-98 Jan-99 Jan-00 Jan-01 Jan-02 Jan-03 Jan-04 Time (month/year)

7. Tommy’s virtual phenotype (Vircotype)

8. SQV/LPV/r without NRTIs selected • Rationale • Favourable PK profiles 1,2 • In vitro synergy 3,4 • Historic data on SQV/RTV 400/400 mg bid 5 • Stephan et al. AIDS 2004; 18:503–8 • Ribera et al. 14th IAC 2002; Abstract TuPeB4545 • Molla et al. Antimicrob Agents Chemother 2002; 46:2249–2253 • Heilek-Snyderet al. 3rd European Resistance Workshop 2005; Abstract 8.4 • Cohen et al. 9th CROI 2002; Abstract 683-T

9. SQV/LPV/r effective but Tommy experienced some metabolic side effects March 2001 starts double boosted regimen: • Lopinavir/r and Fortovase 1000 mg bid without NRTIs • Viral load: < 75 copies/ml • CD4 count: increases to > 500 cells/mm3 again • Generally well tolerated although: • Increase in abdominal fat • Diarrhea – changed to Invirase 1000 mg bid and less diarrhea noted • After one year: Total Chol LDL HDL TG Glucose 230 179 35–45 260 116

10. Successful response to double boosted regimen d4T+3TC EFV+ddI+ABC SQV/LPV/r 800 100,000 700 600 10,000 500 CD4 count (cells/mm3) HIV RNA (log10 copies/ml) 400 1,000 300 100 200 100 0 10 Jul-04 Jul-97 Jul-98 Jul-99 Jul-00 Jul-01 Jul-02 Jul-03 Jan-05 Jan-97 Jan-98 Jan-99 Jan-00 Jan-01 Jan-02 Jan-03 Jan-04 Time (month/year)

11. Tommy’s cardiac risk factors http://hin.nhlbi.nih.gov/atpiii/calculator.asp Age 51 Gender Male Total cholesterol 230 mg/dl HDL cholesterol 37 mg/dl Smoker Yes Systolic blood pressure 140 mm/Hg On hypertension medication No

12. Tommy’s cardiac risk factors http://hin.nhlbi.nih.gov/atpiii/calculator.asp Age 51 Gender Male Total cholesterol 230 mg/dl HDL cholesterol 37 mg/dl Smoker Yes Systolic blood pressure 140 mm/Hg On hypertension medication No Risk score: 21% likelihood of having a heart attack in the next 10 years

13. Saquinavir PK: atazanavir further enhances boosted saquinavir 4000 SQV/r 1600/100 mgqd* SQV/ATV/r 1600/300/100 mg qd* 3000 Geometric mean [SQV] (ng/ml) Cmax increase 42% AUC increase 60% Ctrough increase 112% n = 18 2000 1000 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) * The licensed dosage of saquinavir/r is 1000/100 mg bid Boffito et al. AIDS 2004; 18:1291–7

14. SQV/ATV/r maintains viral suppression, substantial lipid improvements November 2003 changes to: • ATV 300 mg qd + INV 1600 mg qd + RTV 100 mg qd • Viral load remains suppressed • Minimal scleral icterus – of no concern Total Chol LDL HDL Triglycerides At switch 230 179 35–45 260 Now 203 126 47 151

15. SQV/ATV/r maintains viral suppression, substantial lipid improvements November 2003 changes to: • ATV 300 mg qd + INV 1600 mg qd + RTV 100 mg qd • Viral load remains suppressed • Minimal scleral icterus – of no concern Total Chol LDL HDL Triglycerides At switch 230 179 35–45 260 Now 203 126 47 151 Risk score: 14% likelihood of having a heart attack in the next 10 years (down from 21%)

16. 800 100,000 700 600 10,000 500 CD4 count (cells/mm3) HIV RNA (log10 copies/ml) 400 1,000 300 100 200 100 0 10 Jul-04 Jul-97 Jul-98 Jul-99 Jul-00 Jul-01 Jul-02 Jul-03 Jan-05 Jan-97 Jan-98 Jan-99 Jan-00 Jan-01 Jan-02 Jan-03 Jan-04 Time (month/year) Successful response to double boosted regimens d4T+3TC EFV+ddI+ABC SQV/LPV/r SQV/ATV/r

17. The StARS Study • n = 12 patients stable on SQV/LPV/r • Undetectable viral load • Switch to SQV/ATV/r • SQV dose 1200 mg for first 2 weeks • One patient withdrew due to pregnancy • 11/11 patients remain with undetectable viral load SQV/LPV/r 1000/400/100 mg bid SQV/ATV/r 1600/300/100 mg qd Colson et al. 3rd IAS 2005. Poster WePe12.3C20

18. The StARS Study: improved lipids with SQV/ATV/r p = 0.006 p = 0.003 300 Median values (mg/dl) 252 250 220 181 200 p = ns 168 150 p = ns 102 94 100 45 42 50 0 Total Cholesterol LDL HDL Triglycerides SQV/LPV/r baseline SQV/ATV/r Week 24 Colson et al. 3rd IAS 2005. Poster WePe12.3C20

19. Current status andsummary of key points • Doing well on SQV/ATV/r 1500/300/100 mg qd • Maintains viral suppression • Improved lipids • Six pills once daily • Double boosting is an option for patients with: • Limited nucleoside options (resistance/toxicity) • Prior PI experience/resistance