Patterson P, et al. 12th EACS Abstract PS4/4 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, 1 Frank Tomaka, 2 Sabrina Spinosa-Guzman, 3 Diego Miralles 4 and Pedro Cahn 1 1 Fundacion Huesped, Buenos Aires, Argentina; 2 Tibotec Inc, Yardley, PA, USA; 3 Tibotec BVBA, Mechelen, Belgium; 4 PRD West Coast Research Center, San Diego, CA, USA

Patterson P, et al. 12th EACS Abstract PS4/4 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

Patterson P, et al. 12th EACS Abstract PS4/4 1. Squires et al, 5 th IAS Abstract TUAB106-LB; Ripamonti et al, 12th EACS Abstract PS4/1 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/mL 1 ; DRV/r 800/100mg qd monotherapy (84.3%) was non-inferior to DRV/r 800/100mg qd + 2 NRTIs (85.3%)

Patterson P, et al. 12th EACS Abstract PS4/4 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

Patterson P, et al. 12th EACS Abstract PS4/4 TMC114-C227: pilot study design 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/mm 3 at screening No resistance mutations at screening* N=11 (initial enrolment [Panel A]; followed by enrolment of 13 additional patients [Panel B]) DRV/r 800/100mg qd monotherapy Treatment phase (up to 48 weeks) 4 week follow-up period 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 *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. Primary endpoints Week 4: HIV-1 RNA decrease from baseline of >1.0 log 10 copies/mL Week 8: HIV-1 RNA <400 copies/mL in  7 patients Weeks 24 and 48: HIV-1 RNA <50 copies/mL

Patterson P, et al. 12th EACS Abstract PS4/4 13 additional patients to be recruited (Panel B): HIV-1 RNA 20,000–500,000 copies/mL CD4 cell count >100 cells/mm 3  18/24 patients achieve HIV-1 RNA <400 copies/mL Trial stopped if <18/24 patients achieve HIV-1 RNA <400 copies/mL Trial continues After all 24 patients complete 8 weeks of treatment Trial continues as planned to Week 48 Yes No Yes TMC114-C227: stopping rules N=11 (Panel A) (BL VL 10,000 –100,000 copies/mL)  7/11 patients achieve HIV-1 RNA <400 copies/mL After 8 weeks of treatment Trial stopped if <7/11 patients achieve HIV-1 RNA <400 copies/mL No

Patterson P, et al. 12th EACS Abstract PS4/4 TMC114-C227: patient demographics and baseline characteristics N=7 Baseline demographics Male, n6 Median age, years (range)39 (30–59) Caucasian/Hispanic, n6/1 Disease characteristics Median (range) baseline HIV-1 RNA, copies/mL52,183 (20,882–145,002) Median CD4 cell count, cells/mm 3 (range)145 (64–353) Mean duration of known HIV infection, years (± SD)5.9 (4.32) 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/mm 3 at screening as required for eligibility)

Patterson P, et al. 12th EACS Abstract PS4/4 TMC114-C227: patient disposition 45 patients screened 7 patients received DRV/r monotherapy 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/mm 3 2 due to acute hepatitis HAV IgM+ and HBsAg+ 2 withdrew consent 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 All 7 patients reached Week Week Screening

Patterson P, et al. 12th EACS Abstract PS4/4 TMC114-C227: observed change in log 10 plasma HIV-RNA from baseline – individual patient data 400 copies/mL D/C 001, 002, 003 D/C 004 D/C 005, 006 D/C 007 Time (weeks) 50 copies/mL* 100,000 copies/mL HIV-1 RNA (log 10 copies/mL) Screening *HIV-1 RNA <50 copies/mL was imputed as 49 copies/mL

Patterson P, et al. 12th EACS Abstract PS4/4 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 HIV-1 RNA (log 10 copies/mL) Screening D/C 001, 002, 003 D/C 004 D/C 005, 006 D/C *HIV-1 RNA <50 copies/mL was imputed as 49 copies/mL Time (weeks) 50 copies/mL*

Patterson P, et al. 12th EACS Abstract PS4/4 50 copies/mL* 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 HIV-1 RNA (log 10 copies/mL) Time (weeks) Screening D/C 001, 002, 003 D/C 004 D/C 005, 006 D/C Post-trial intensification *HIV-1 RNA <50 copies/mL was imputed as 49 copies/mL Follow-up time (weeks) 0

Patterson P, et al. 12th EACS Abstract PS4/4 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 Baseline HIV-1 RNA (copies/mL) Endpoint Developing mutations at endpoint PatientVisit HIV-1 RNA (copies/mL)PI mutationsRT mutations ,002Week 321,369 I13V, K14R, I64L, I72V* ,502Week 121,113- E138Q, T200A, Q207H *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

Patterson P, et al. 12th EACS Abstract PS4/4 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

Patterson P, et al. 12th EACS Abstract PS4/4 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 log 10 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

Patterson P, et al. 12th EACS Abstract PS4/4 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

Patterson P, et al. 12th EACS Abstract PS4/4 TMC114-C227: conclusions All patients achieved >1 log 10 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

Patterson P, et al. 12th EACS Abstract PS4/4 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