A Phase II, open-label trial in treatment-naïve, HIV-1-infected patients who received DRV/r as induction monotherapy

1. A Phase II, open-label trial in treatment-naïve, HIV-1-infected patients who received DRV/r as induction monotherapy Patricia Patterson,1 Alejandro Krolewiecki,1Frank Tomaka,2 Sabrina Spinosa-Guzman,3Diego Miralles4 and Pedro Cahn1 1Fundacion Huesped, Buenos Aires, Argentina;2Tibotec Inc, Yardley, PA, USA; 3Tibotec BVBA, Mechelen, Belgium; 4PRD West Coast Research Center, San Diego, CA, USA

2. Pedro Cahn – Disclosures • Investigator: Abbott; Avexa; Boehringer-Ingelheim; BMS; GSK; Myriad; Merck; Pfizer; Pharmasset; Tibotec; Schering-Plough • Speaker: Abbott; BMS; Gilead; Merck; Pfizer; Tibotec • Scientific Advisor: Avexa; GSK; Myriad; Merck; Pfizer; Tibotec, Schering-Plough

3. Background • Simplifying ARV therapy for HIV-infected patients is important to ensure long-term treatment adherence, minimise toxicities and reduce costs. Strategies could include: • induction monotherapy • maintenance monotherapy • Maintenance monotherapy data with once-daily DRV/r in virologically suppressed patients have shown encouraging results • MONET: 48-weeks: HIV-1 RNA <50 copies/mL1; DRV/r 800/100mg qd monotherapy (84.3%) was non-inferior to DRV/r 800/100mg qd + 2 NRTIs (85.3%) 1. Squires et al, 5th IAS 2009. Abstract TUAB106-LB; Ripamonti et al, 12th EACS 2009. Abstract PS4/1

4. TMC114-C227 pilot study in ARV treatment-naïve patients: objectives • TMC114-C227 was an exploratory pilot study designed to evaluate once-daily DRV/r induction monotherapy in treatment-naïve patients • stringent inclusion/exclusion criteria were applied to decrease the risk of virological failure • virological responses were closely monitored • rigorous criteria were applied to discontinue treatment immediately if there was evidence that treatment did not result in complete viral suppression

5. TMC114-C227: pilot study design • Pilot, open-label, uncontrolled, Phase II trial to investigate the sustained antiretroviral activity of DRV/r induction monotherapy in 24 treatment-naïve, HIV-1-infected adult patients over 48 weeks • ARV-naïve, HIV-1-infected adult patients 18yrs old • Screening HIV-1 RNA 10,000–100,000 copies/mL (Panel A) • CD4 cell count >100 cells/mm3 at screening • No resistance mutations at screening* • N=11 (initial enrolment [Panel A]; followed by enrolment of 13 additional patients [Panel B]) Treatment phase (up to 48 weeks) 4 week follow-up period DRV/r 800/100mg qd monotherapy • Primary endpoints • Week 4: HIV-1 RNA decrease from baseline of >1.0 log10 copies/mL • Week 8: HIV-1 RNA <400 copies/mL in 7 patients • Weeks 24 and 48: HIV-1 RNA <50 copies/mL *The following polymorphisms were allowed as they have no known effect on DRV susceptibility: I13V, K20I/M/R, M36I/V, D60E, I62V, L63P, A71T/V, V77I and I93L.

6. After all 24 patients complete 8 weeks of treatment Trial continues Yes • 13 additional patients to be recruited (Panel B): • HIV-1 RNA 20,000–500,000 copies/mL • CD4 cell count >100 cells/mm3 No Trial continues as planned to Week 48 18/24 patients achieve HIV-1 RNA <400 copies/mL Trial stopped if <7/11 patients achieve HIV-1 RNA<400 copies/mL Yes No Trial stopped if <18/24 patients achieve HIV-1 RNA <400 copies/mL TMC114-C227: stopping rules N=11 (Panel A)(BL VL10,000–100,000 copies/mL) After 8 weeks of treatment 7/11 patients achieve HIV-1 RNA <400 copies/mL

7. TMC114-C227: patient demographics and baseline characteristics • 3 patients had HIV-1 RNA ≥100,000 copies/mL at baseline (all 3 had HIV-1 RNA <100,000 at screening, required for eligibility) • 2 patients had CD4 cell count <100 cells/mm3 at baseline (both patients had CD4 cell count >100 cells/mm3 at screening as required for eligibility)

8. TMC114-C227: patient disposition • 38 excluded (due to ≥1 failing criteria): • 21 due to failure to meet screening HIV-1 RNA criteria (16 with HIV-1 RNA >100,000 copies/mL; 5 with HIV-1 RNA <10,000 copies/mL) • 22 due to failure to meet screening resistance criteria • 5 due to CD4 <100 cells/mm3 • 2 due to acute hepatitis HAV IgM+ and HBsAg+ • 2 withdrew consent 45 patients screened Screening 7 patients received DRV/r monotherapy 0 All 7 patients reached Week 12 12 Week 24 Trial terminated at Week 32 3 patients reached the Week 32 visit. Decision to terminate trial based on difficulties meeting inclusion criteria and trend to insufficient number of patients achieving virological endpoints at Week 32 36

9. TMC114-C227: observed change in log10 plasma HIV-RNA from baseline – individual patient data 6 100,000 copies/mL 5 4 HIV-1 RNA (log10 copies/mL) 3 400 copies/mL 2 50 copies/mL* 1 0 32 2 Screening 0 1 4 8 12 16 20 24 D/C005, 006 D/C007 D/C004 D/C001, 002, 003 Time (weeks) *HIV-1 RNA <50 copies/mL was imputed as 49 copies/mL

10. TMC114-C227: post-trial period – individual patient data • Post-trial, all 7 patients received combination therapy with DRV/r, lamivudine plus zidovudine. One patient was switched to tenofovir plus lamivudine due to anaemia • All patients achieved HIV-1 RNA <50 copies/mL by 12 weeks after intensification 6 5 4 HIV-1 RNA (log10 copies/mL) 3 2 50 copies/mL* 1 D/C004 D/C001, 002, 003 D/C005, 006 D/C007 0 32 0 4 8 12 16 20 24 Screening Time (weeks) *HIV-1 RNA <50 copies/mL was imputed as 49 copies/mL

11. TMC114-C227: post-trial period – individual patient data • Post-trial, all 7 patients received combination therapy with DRV/r, lamivudine plus zidovudine. One patient was switched to tenofovir plus lamivudine due to anaemia • All patients achieved HIV-1 RNA <50 copies/mL by 12 weeks after intensification 6 Post-trial intensification 5 4 HIV-1 RNA (log10 copies/mL) 3 2 50 copies/mL* 1 D/C004 D/C001, 002, 003 D/C005, 006 D/C007 0 32 48 32 0 4 8 12 16 20 24 0 4 12 16 24 Screening Time (weeks) Follow-up time (weeks) *HIV-1 RNA <50 copies/mL was imputed as 49 copies/mL

12. TMC114-C227: resistance determinations • Post-screening resistance data were available for two patients with viraemia and paired baseline/endpoint genotypes • no DRV RAMs developed • no IAS-USA major PI mutations developed *none of these mutations correspond to DRV RAMs or IAS-USA major PI mutations Resistance testing was performed locally; only 2 samples were received for post screening testing

13. TMC114-C227: summary of safety • Most common adverse events (AEs, all grades, regardless of causality and occurring in >2 patients) were: • nasopharyngitis (n=6) • diarrhoea (n=4) • asthenia (n=3) • No grade 3 or 4 AEs or laboratory abnormalities were reported • There were no serious AEs or discontinuations due to AEs • No new safety information emerged compared with the safety profile of once-daily DRV/r from larger trials

14. TMC114-C227: overall summary Only 7 of the 11 patients planned for the first phase could be enrolled At Week 4, all 7 patients achieved 1 log10 HIV-1 RNA reduction from baseline and maintained it during the treatment phase The trial was discontinued at Week 32 as it was unlikely that it would reach its predetermined virological endpoints and had a high screening failure rate Dosing with once-daily DRV/r was generally well-tolerated Patients with paired baseline/endpoint genotypes did not develop DRV mutations or IAS-USA major PI mutations on failure All patients subsequently achieved HIV-1 RNA <50 copies/mL following intensification with NRTIs

15. TMC114-C227: study limitations • TMC114-C227 was a small pilot study • an insufficient number of patients could be enrolled due to restrictive inclusion/exclusion criteria • Only 7 of the 11 planned patients in Panel A could be enrolled • The pre-planned stopping rules may have been too stringent • although all enrolled patients met the HIV-1 RNA screening criterion, at the time of the baseline visit 3 of the 7 patients had HIV-1 RNA >100,000 copies/mL

16. TMC114-C227: conclusions • All patients achieved >1 log10 HIV-1 RNA reduction by Week 4 but complete viral suppression was not consistently achieved on induction monotherapy • Due to study limitations, definitive conclusions cannot be drawn from this pilot study • After the study, all patients achieved HIV-1 RNA <50 copies/mL with intensification of therapy

17. Acknowledgements • The authors express their gratitude to the patients who participated in the study, as well as the study centre staff and the TMC114-C227 study team • The authors would also like to thank Sandra De Meyer, Tom Van De Casteele and Vanitha Sekar from Tibotec for their contributions to the data analyses and interpretation and Eric Lefebvre, Ralph DeMasi, Gaston Picchio and Andrew Hill for their important contributions to the presentation • Editorial support was provided by Catherine Elliott of Gardiner-Caldwell Communications, Macclesfield, UK; this support was funded by Tibotec