Tenofovir Alafenamide (TAF)

Transcription

1 Frontier AIDS Education and Training Center Tenofovir Alafenamide (TAF) Brian R. Wood, MD Assistant Professor of Medicine, University of Washington Medical Director, Frontier AETC ECHO January 28, 2016 This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient.

2 Tenofovir Alafenamide (TAF) 1) What is TAF? 2) Summary of clinical trials, approval and indications to date 3) Review of key clinical trial data 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: atazanavir, DRV: darunavir RPV: rilpivirine, EFV: efavirenz COBI: cobicistat

3 What is tenofovir alafenamide (TAF)?

4 Tenofovir disoproxil fumarate (TDF) vs. Tenofovir alafenamide (TAF) Gut Plasma Lymphoid Cells TDF TDF TFV TFV Cathepsin A P TFV-MP TAF TAF 91% lower plasma TFV levels with TAF TAF P TFV-DP Active drug TDF = tenofovir disoproxil fumarate; TFV = tenofovir; MP = monophosphate; DP = diphosphate

5 Summary of Clinical Trials, Approval and Indications to Date

6 Summary of Key Tenofovir Alafenamide (TAF) Studies Phase 3 Trials of E/C/F/TAF for HIV Treatment: - GS 104/111: E/C/F/TAF vs. E/C/F/TDF in treatment-naïve - GS 109: Switch to E/C/F/TAF from standard TDF-containing ART - GS 112: Switch to E/C/F/TAF in setting of renal impairment - Switch to E/C/F/TAF + DRV to replace salvage ART Ongoing Phase 3 HIV Treatment Trials - Switch to FTC/TAF from FTC/TDF (both with standard 3 rd agent) - Switch to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF - DRV/COBI/FTC/TAF in treatment-naïve or experienced - GS-9883/FTC/TAF in treatment-naïve or experienced Phase 3 Hepatitis B (HBV) Treatment Trials - GS 108/110: TAF vs. TDF for HBV monoinfection - Switch to E/C/F/TAF for HIV-HBV coinfection

7 Approved Formulations and Indications to Date E/C/F/TAF (Genvoya) approved Nov. 5, 2015 Indications: 1) Initial regimen for treatment-naïve individuals 2) To replace current regimen for those with HIV RNA <50 copies/ml on a stable regimen for at least 6 months with no history of treatment failure and no resistance to the individual components Source: Genvoya Package Insert, gilead.com

8 Review of Key Clinical Trial Data GS104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART

9 GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART Study Design Protocol - 2 double-blind RCT s - Treatment-naïve HIV-1 infected adults with CrCl >50 ml/min outpatient centers, 16 countries - Randomized 1:1 to each study arm - Outcomes: proportion with HIV RNA <50 copies/ml at 48 weeks and prespecified renal and bone changes - Results stratified by pre-treatment HIV RNA level and CD4, as well as age, race, and gender E/C/F/TAF + Placebo (n = 866) E/CF/TDF + Placebo (n = 867) Source: Sax PE et al. Lancet 2015; 385:

10 %HIV RNA <50 copies/ml GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART Proportion with HIV RNA <50 copies/ml at 48 Weeks E/C/F/TAF E/C/F/TDF 92.0 * Overall HIV RNA 100,000 HIV RNA > 100,000 *Statistically significant difference Baseline HIV RNA Level Source: Sax PE et al. Lancet 2015; 385:

11 GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART Median % Change from Baseline to Week 48 E/C/F/TAF E/C/F/TDF P Value Estimated GFR (ml/min) <0.001 Urine protein:creatinine < Urine albumin:creatinine < Retinol binding protein:creatinine < β-2-microglobulin:creatinine < Hip bone mineral density < Spine bone mineral density < Source: Sax PE et al. Lancet 2015; 385:

12 GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART Median Change from Baseline to Week 48 E/C/F/TAF (N=306) E/C/F/TDF (N=153) P Value Total cholesterol <0.001 LDL <0.001 HDL <0.001 Triglycerides Total cholesterol:hdl ratio Proportion who initiated a lipid-modifying agent: 2.9% TAF arm, 3.6% TDF arm Source: Sax PE et al. Lancet 2015; 385:

13 Review of Key Clinical Trial Data GS 109: Switching from TDF to TAF

14 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 TDFcontaining regimen (their 1 st 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) *Primary endpoint: HIV RNA <50 copies/ml at 48 weeks Source: Mills A et al. Lancet Infect Dis Jan;16(1):43-52.

15 % HIV RNA <50 copies/ml GS-109: Switch from TDF to TAF 48 Week Data: Proportion with HIV RNA <50 copies/ml E/C/F/TAF Prior TDF Regimen P<0.001 P=0.02 P=0.02 P=NS All prior regimens Prior TDF/FTC/EFV Source: Mills A et al. Lancet Infect Dis Jan;16(1): Prior TDF/FTC + ATV/booster Prior E/C/F/TDF

16 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 Serum creatinine (mean, mg/dl) <0.001 Urine protein:creatinine <0.001 Urine albumin:creatinine <0.001 Retinol binding protein:creatinine <0.001 Beta-2-microglobulin:creatinine <0.001 Hip bone mineral density <0.001 Spine bone mineral density <0.001 Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.

17 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 <0.001 LDL <0.001 HDL Triglycerides <0.001 Total cholesterol:hdl ratio 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.

18 Review of Key Clinical Trial Data GS 112: Switching to E/C/F/TAF in Setting of Renal Impairment

19 GS 112: Switching to E/C/F/TAF in Renal Impairment Study Design Protocol - Single arm, open-label safety and efficacy trial - HIV-infected adults with HIV RNA <50 copies/ml for at least 6 months - egfr stable at ml/min (no change in renal function or medical management of renal disease for at least 3 months) Switch to E/C/F/TAF (n = 242) *Primary endpoint: change from baseline in egfr measured in various ways Source: Pozniak A et al. J Acquir Immune Defic Syndr Nov 30. [Epub ahead of print]

20 GS 112: Switching to E/C/F/TAF in Renal Impairment Baseline Characteristics egfr <50 (n=80) egfr >50 (n=162) Total (n=242) Median age Age >65 (%) Female (%) Black or African descent (%) CD4 count (median) Pre-switch TDF use (%) Hypertension (%) Diabetes (%) Median egfr (CG, ml/min) Median egfr (CKD-epi, ml/min) Significant proteinuria (%) Significant albuminuria (%) Source: Pozniak A et al. J Acquir Immune Defic Syndr Nov 30. [Epub ahead of print]

21 GS 112: Switching to E/C/F/TAF in Renal Impairment Week 48 Change from Baseline Total (n=242) egfr <50 (n=80) egfr >50 (n=162) TDF- Containing (n=158) Non-TDF- Containing (n=84) egfr (CG, ml/min) egfr (CKD-EPI, ml/min) Urine protein:cr ratio * 0 Urine albumin:cr ratio * -4 RBP:Cr ratio ,374* -31 β-2 microglobulin:cr ratio -1,349-3,270* -178 *Statistically significant change Source: Pozniak A et al. J Acquir Immune Defic Syndr Nov 30. [Epub ahead of print]

22 SUMMARY TAF consistently demonstrates high virological efficacy with improvements in proximal tubulopathy and bone mineral density markers compared to TDF; lipids increase though that is of unclear clinical significance Glass half full perspective: this is a promising advance in ART and offers significant improvements over TDF that will lead to fewer long-term adverse events, especially as our patients age Glass half empty perspective: follow-up time is limited and does not include clinically significant events (like fractures) and, as with TDF, it will take years to know if TAF causes clinically significant renal impairment or not