Significance of ARV Pharmacokinetics

Data Presentation

Time Post-dose (hours) PK substudy – week 4 data (n=9) (mean ± SD) DRV Plasma Conc (ng/mL) EC 50 = 55 ng/mL for wild-type virus (adjusted for protein binding) ,000 10,000 De Jesus E, et al. 47th ICAAC, Chicago, 2007 Abstract 718b. ARTEMIS: Favorable PK for DRV Once-Daily

ARTEMIS: Predictors of Success Sub-analysis of factors associated with successful virologic response demonstrated non-adherent pts did significantly better on DRV/r than LPV/r Proportion of Patients in ARTEMIS with HIV-1 RNA <50 copies/mL by Average Adherence* *Adherence based on average % adherence Week 4 through Week 96 Nelson M, et al. 16th CROI, Montreal, Canada, Abst AdherentSub-optimally adherent LPV/r AdherentSub-optimally adherent DRV/r 78% (n=252) 53% (n=70) P< % (n=269) 76% (n=55) P= <50 copies/mL at Week 96

Intracellular and Plasma Half-lives of ARVs Used in FOTO Study Hours 24 hours Cohen C, et al. 9th ICDTHI, Glasgow, Abst. O214.

FOTO: Comparison of Continuous Therapy with 5 Days On, 2 Days Off Pts with HIV RNA <50 copies/mL on TDF / FTC / EFV (N=60) No virologic failures seen (due to prolonged ½ life of regimen?) Number / pattern of “blips” similar No significant difference in CD4 count changes Strong pt preference by Likert Scale (9.5/10) for FOTO Cohen C, et al. 9th ICDTHI, Glasgow, Abst. O214. Continue daily ARV treatmentChange to Five days On; Two Off Primary Outcome: 24 weeks (Missing = Excluded) 97% 96% 87% 86% 88% 90% 93% 100% **P< to exclude inferiority of FOTO *

Relationship between adherence and maintenance of virologic suppression evaluated in subset of REACH cohort: homeless or marginally housed with HIV RNA <50 c/mL (n=221) VL and adherence by unannounced pill counts measured monthly ART: NNRTI (38%); Boosted PI (32%) With longer duration of viral suppression, adherence >50% becomes more likely to maintain viral suppression Longer Duration of Virologic Suppression Decreases Risk for Virologic Failure Rosenblum M, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 583.

BENCHMRK: RAL Plasma Pharmacokinetics Are Not Predictive of Response RAL Effective Across Range of Trough Levels Trough concentrations do not predict RAL effectiveness Prolonged pre-integration complex binding may explain the lack of correlation with trough concentration Miller M, et al. 48th ICAAC/46th IDSA, Washington, DC, Abst. H-898 % patients with HIV RNA <400 c/mL GM Observed C 12hr (nM) GM Observed C 12hr <33 nM (~in vitro IC 95 )

Pharmacokinetic Study of ATV 200, 300, 400 mg BID in Healthy Subjects ATV approved doses: 400 QD (naïve) 300/100 QD (naïve, experience) Open-label, 3-way randomized crossover study with healthy volunteers (n=18) Designed to assess the PK, safety and tolerability of ATV 200, 300 and 400 BID without RTV Cmin for ATV 300mg and 400mg BID similar to ATV/r 300/100mg QD Geometric Mean 10 x EC 90 EC 90 Historical ATV 400 mg QD (N=106) ATV 200 mg BID (N=17) ATV 300 mg BID (N=17) ATV 400 mg BID (N=17) Historical ATV/r 300/100 mg QD (N=116) Atazanavir Cmin (ng/mL) ATV and ATV/r C min Zhu L, et al. 48th ICAAC/46th IDSA; Washington, DC; October Abst. A-952

ATV Pharmacokinetics: Study Results ATV 300 mg BID was the most similar to ATV/r 300/100 mg QD based on PK, magnitude of PR prolongation and hyperbilirubinemia. ATV 200 mg BID ATV 300 mg BID ATV 400 mg BID Most Frequent AEs, n (%) First Degree AV Block01 (5.6)10 (59) Prolonged QRS Complex005 (29) Grade ¾ Lab Abnormalities, n (%) Total Bilirubin, Grade 39 (50)10 (56)7 (41) Total Bilirubin, Grade 404 (22)9 (53) Atazanavir (ng/mL) 300 mg BID AM 300 mg BID PM Historical ATV/r 300/100 mg QD (N=116) Time after AM dose (h) 10x EC 90 Comparison of PK of ATV 300mg BID with ATV/r 300/100mg QD Adverse Events Historical Cmin: ATV/r 300/100 mg QD (N=116) Zhu L, et al. 48th ICAAC/46th IDSA; Washington, DC; October Abst. A-952

PK and Safety of BID ATV 300mg and RAL 400mg in Healthy Subjects ATV inhibits UGT1A1 and increases RAL systemic exposure 22 subjects dosed with RAL 400 BID (days 1-5)  ATV 300 BID (days 6-12)  RAL/ATV BID (days 13-26) All ATV Cmin were >10 times higher than the EC90 (14ng/mL) RAL increased to the extent observed when dosed with ATV/r 300/100mg ATV + RAL may provide a nucleoside and RTV-sparing option and a pilot study in naïve patient is currently underway Mean ATV Plasma Concentrations Time (h) Atazanavir Concentrations (ng/mL) Mean RAL Plasma Concentrations Time (h) Raltagravir Concentrations (ng/mL) Zhu L, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 696

GS-9350: PK Enhancement without Ritonavir GS-9350: Potent, specific inhibitor of CYP3A with no anti-HIV activity Boosting of EVG similar to RTV GS-9350 (150 mg) maintained EVG trough concentrations 11-fold above the protein binding-adjusted IC95 (44.5 ng/mL) Well tolerated with minimal impact on adipocytes or insulin resistance Fixed-dosed combination of GS EVG + TDF/FTC being explored Bars represent geometric mean (±95% Cl) 100mg150mgRTV GS-9350 Elvitegravir C tau (ng/mL) Kearnew B, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 40.

SPI-452: A Potential Replacement for Ritonavir SPI-452: Potent CYP3A inhibitor in preclinical evaluation PI boosting similar to RTV DRV ↑37 fold, ATV ↑12 fold, and levels remain significantly increased 24 hours after last dose Moderate tolerability issues with headache and nausea, diarrhea Solubility issues are a concern, as current formulation is a liquid Maximum achievable levels PI Enhancement in Human Liver Microsomes AUC* * Based on percent of substrate remaining vs time Gulnik S, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 41.

Low Levels of HIV RNA Associated with Neurocognitive Impairment Study to evaluate relationships between HIV RNA in CSF, ARV penetration in CSF and neuropsych performance Subjects with HIV RNA in CSF <50 c/mL (n=300) Test for HIV RNA with NucliSens EasyQ assay (sensitivity = 2 c/mL) Results 26% of subjects had HIV RNA in CSF but not in plasma Detection of low level HIV RNA in CSF associated with lower ARV CSF Penetration Effectiveness (CPE) score Poorer neuropsych performance when HIV RNA detected in CSF but NOT plasma compared to subjects with HIV RNA in CSF and plasma Relationship Between ARV CNS Penetration and HIV RNA in CSF Neurocognitive Function and HIV RNA in CSF and Plasma Proportion26%74% CSF >2 c/mLYesYes Plasma >2 c/mLNoYes P= Global Rating d=0.71 P=0.006 OR = 1.7 P= CPE Rank, Proportion ≥1.5 Letendre S, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 484b. HIV RNA in CNS >2 c/mL

Proposed ARV CNS Penetration-Effectiveness Scores Letendre S, et al. Arch Neurol 2008;65:65-70; Letendre S, personal communication. Penetration RankScore 1 NRTIsNNRTIsPIs Other Classes Good1 Abacavir Zidovudine Delavirdine Nevirapine Indinavir Indinavir/ritonavir Lopinavir/ritonavir Darunavir/ritonaivr Maraviroc Fair0.5 Emtricitabine Lamivudine Stavudine Efavirenz Amprenavir/ritonavir Atazanavir Atazanavir/ritonavir Raltegravir Poor0 Didanosine Tenofovir Zalcitabine Amprenavir Nelfinavir Ritonavir Saquinavir Saquinavir/ritonavir Tipranavir/ritonavir Enfuvirtide

Significance of ARV Pharmacokinetics Debate/Discussion