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

2. 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

3. 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

4. Switching from TDF to TAF

5. 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, TDF/FTC + ATV/booster TDF/FTC/EFV 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.

6. 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.

7. 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.

8. 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.

9. 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.

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

11. 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 San Diego. Abstract 726.

12. 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 San Diego. Abstract 726.

13. 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 San Diego. Abstract 726.

14. 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 San Diego. Abstract 726.

15. 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 San Diego. Abstract 726.

16. 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 San Diego. Abstract 726.

17. 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.