ID Week Review 2015 Brian R. Wood, MD Assistant Professor of Medicine, University of Washington Medical Director, Frontier AETC ECHO October 2015

ID Week Review 2015 1) Switching from TDF to TAF 2) Simplifying salvage therapy to E/C/F/TAF + DRV Abbreviations: TDF: tenofovir disoproxil fumarate TAF: tenofovir alafenamide E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide ATV/booster: boosted atazanavir DRV: darunavir RPV: rilpivirine

Tenofovir disoproxil fumarate (TDF) vs. Tenofovir alafenamide (TAF) Gut Plasma Lymphoid Cells TDF TDF TFV TFV P Cathepsin A TFV-MP Other advantage is effective at very low dose (25 mg unboosted, 10 mg boosted with cobicistat) so easily coformulated TAF TAF TAF P TFV-DP Active drug 91% lower plasma TFV levels with TAF TDF = tenofovir disoproxil fumarate; TFV = tenofovir; MP = monophosphate; DP = diphosphate

Switching from TDF to TAF

GS-109: Switching from TDF to TAF Study Design Protocol - Randomized, open-label study - HIV-infected adults with HIV RNA <50 copies/mL for >48 weeks on a TDF- containing regimen (their 1st regimen) - eGFR >50 mL/min - Total N = 1,436 - 601 TDF/FTC + ATV/booster - 376 TDF/FTC/EFV - 459 E/C/F/TDF - Randomized 2:1 Switch to E/C/F/TAF (n = 959) Continue current TDF-based regimen (n = 477) *Patients from 6 other Gilead studies *Largest switch study to date *2 study arms were well balanced except criticism: <10% women in both arms *Study will continue to week 96 *Primary endpoint: HIV RNA <50 copies/mL at 48 weeks Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.

GS-109: Switch from TDF to TAF 48 Week Data: Proportion with HIV RNA <50 copies/mL P<0.001 P=0.02 P=0.02 P=NS *Presented at IAS/Vancouver earlier this year *All statistically significant differences except prior E/C/F/TDF  now will examine that arm more closely *No significant difference in # of virologic failures or in patient reported side effects; mild increased depression and increased AST in TDF arm *Lets look more closely at differences in renal, bone and lipid changes Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.

GS-109: Switch from TDF to TAF Median % Change from Baseline to Week 48 E/C/F/TAF (N=306) E/C/F/TDF (N=153) P Value Urine protein:creatinine -16.2 +13.7 <0.001 Urine albumin:creatinine -17.7 +7.7 Retinol binding protein:creatinine -28.6 +27.4 Beta-2-microglobulin:creatinine -43.3 +20.8 Hip bone mineral density +1.15 -0.24 Spine bone mineral density +1.33 -0.50 *Key = only one agent in regimen different so can compare TDF to TAF directly -Patients switching to TAF had significant decrease in serum creatinine, markers of general and tubular proteinuria, and fractional excretion of phosphate (starting at week 2) and significantly different at week 48; serum creatinine decreased almost immediately *2 discontinuations for increase in serum creatinine, both in TDF arm *RBP and beta-2-microglobulin are sensitive markers specifically for proximal tubular proteinuria *Not shown but also saw significant improvements in fractional excretion phosphate *Not shown but over time, proportion with normal BMD in TAF group improved (as compared to those with osteopenia or osteoporosis) Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.

GS-109: Switch from TDF to TAF Median Change from Baseline to Week 48 E/C/F/TAF (N=306) E/C/F/TDF (N=153) P Value Total cholesterol +21 +2 <0.001 LDL +13 -5 HDL +3 -1 0.01 Triglycerides +23 -7 Total cholesterol:HDL ratio +0.3 +0.1 0.41 Proportion who initiated a lipid-modifying agent: 7.8% TAF arm, 6.5% TDF arm Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.

GS-109: Switch from TDF to TAF Conclusion: “At Week 48, patients who switched from E/C/F/TDF to E/C/F/TAF remained on treatment and maintained high virologic control, had significantly improved hip/spine BMD, serum creatinine, and had significantly less general proteinuria and specific proximal tubular proteinuria than those remaining on E/C/F/TDF. Longer term data are needed to understand the clinical relevance of lipid changes in the TAF arm.” Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.

Simplifying Salvage Therapy to E/C/F/TAF + DRV

Simplifying Salvage Therapy to E/C/F/TAF + DRV Study Design Protocol - N = 136 HIV-infected adults - Randomized, open-label study - HIV RNA <50 copies/ml for >4 months on a DRV-containing regimen - >2 prior episodes of virologic failure and >2-class drug resistance - No DRV RAM’s, no INSTI resistance, <3 TAM’s, no Q151M or T69ins - eGFR >50 mL/min - Randomized 2:1 Simplify to E/C/F/TAF + DRV (n = 89) Continue current ART (n = 46) -no INSTI resistance documented or taking RAL and suppressed -primary endpoint: HIV RNA <50 copies at 24 weeks; secondary endpoints = efficacy at 48 weeks and safety *Abbreviations: DRV = darunavir, RAM = resistance associated mutation, INSTI = integrase strand transfer inhibitor, TAM’s = thymidine analogue mutations Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.

Simplifying Salvage Therapy to E/C/F/TAF + DRV Characteristics E/C/F/TAF + DRV (N=89) Baseline Regimen (N=46) Median age, years 49 47 Male 82 61 Black (or African descent) 39 57 Median CD4 count, cells/mL 519 518 Median eGFR, mL/min (Cockroft-Gault) 99 100 Median # pills per day in ART regimen 5 >6 pills per day in ART regimen, % 40 37 At least BID dosing, % 65 Tenofovir, % 54 Raltegravir, % 56 50 2 class / 3 class resistance, % 70 / 26 74 / 20 M184V/I / K65R, % 85 / 20 78 / 30 NNRTI resistance / PI resistance 89 / 38 87 / 28 **Strategic simplification in treatment-experienced individuals with resistance and high pill burden -median age approximately 15 years older than in treatment-naïve trials **Darunavir pharmacokinetic study Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.

Simplifying Salvage Therapy to E/C/F/TAF + DRV Concern for lower levels of elvitegravir and darunavir when co-administered with cobicistat Pharmacokinetic substudy in 15 participants Plasma collected over 24-hour period between weeks 2-8 Post-dose steady state concentrations of TAF, TFV, darunavir, and elvitegravir maintained Trough concentrations 10-20x higher than inhibitory concentrations Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.

Simplifying Salvage Therapy to E/C/F/TAF + DRV No participants in E/C/F/TAF + DRV developed resistance; 1 participant with viral rebound (week 36) in BR arm developed new M184V + K65R 2 failures in switch arm had low-level viremia and suppressed on same regimen in extension beyond 48 weeks Superior at week 48 at both <50 copies and <20 copies Source: Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.

Simplifying Salvage Therapy to E/C/F/TAF + DRV Median % Change from Baseline to Week 48 E/C/F/TAF + DRV (N=89) Baseline Regimen (N=46) P Value eGFR +7.4 +3.9 0.18 Urine protein:creatinine -27 +5 <0.001 Retinol binding protein:creatinine -17 +14 Beta-2-microglobulin:creatinine -29 +13 Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.

Simplifying Salvage Therapy to E/C/F/TAF + DRV Conclusion: “For treatment-experienced individuals with >2 class resistance on complex, high-pill burden regimens, switching to E/C/F/TAF + DRV provides a simple, once-daily, two-pill option with superior efficacy and comparable tolerability.” Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.

Update on FDA New Drug Applications for TAF E/C/F/TAF: target FDA action date Nov 5, 2015 TAF/FTC/RPV: to be reviewed by FDA around Jan 2016 TAF/FTC (2 doses): target action date April 7, 2016 DRV/C/F/TAF: to be determined… *for those treating hep C, there was a presentation on the first 2 and interactions with LDP/SOF and there were no significant interactions or dose modifications needed *striving Source: Gilead Sciences, Inc. Press Release, July 2015.