CROI 2015: Treatment and Cure Highlights

Transcription

1 NORTHWEST AIDS EDUCATION AND TRAINING CENTER CROI 2015: Treatment and Cure Highlights Shireesha Dhanireddy Robert Harrington March 17, 2014 No financial conflicts of interest

2 Outline Treatment Studies - Tenofovir alafenamide (TAF) in a single- tablet regimen in inidal HIV- 1 infecdon (Abstract # 113LB) - Renal and bone TAF vs tenofovir disoproxil fumarate (TDF) (Abstract # 143LB) Cure - Immunoprophylaxis by gene transfer (Abstract #66)

3 Tenofovir Alafenamide

4 Sax P et al, CROI 2015, Abstract 143LB TAF vs TDF:

5 Background TDF causes significant renal and bone toxicity TDF 300mg = TAF 25mg - But 90% lower circuladng plasma TFV while maintaining high viral acdvity Phase 2 study: - Comparable efficacy - TAF less renal and bone effects Sax P et al, CROI 2015, Abstract 143LB

6 Study Design Week Primary Endpoint Tx- Naïve Adults HIV- 1 RNA > 1000 c/ml egfr > 50 ml/min 1:1 N=866 N=867 E/C/F/TAF qday E/C/F/TDF qday (Stribild) 2 phase 3 randomized, double- blind, double- dummy, acdve- controlled studies GS104 (N. America, EU, Asia); GS 111 (N. America, EU, LaDn America) Primary endpoint propordon with HIV- 1 RNA < 50 c/ml Week 48 safety endpoints serum creadnine, proteinuria, hip BMD, spine BMD Sax P et al, CROI 2015, Abstract 143LB Wohl D et al, CROI 2015, Abstract 113LB

7 Baseline CharacterisDcs E/C/F/TAF E/C/F/TDF Median age, year Sex, % Male Female Race/ethnicity, % Black or African Hispanic Median VL, log % with VL >100K Median CD4 count % with CD4 count < Median egfr % with Proteinuria (any grade) Sax P et al, CROI 2015, Abstract 143LB ; Wohl D et al, CROI 2015, Abstract 113LB

8 TAF vs TDF Screened (n=2175) TAF Arm (n=866) TDF arm (n=867) 95% on treatment (n=821) At 48 weeks 92% on treatment (n=796) Sax P et al, CROI 2015, Abstract 143LB ; Wohl D et al, CROI 2015, Abstract 113LB

9 TAF is non- inferior to TDF Week 48 Efficacy Data Wohl D et al, CROI 2015, Abstract 113LB

10 Week 48 Efficacy Data Significantly greater increase in CD4 count in TAF arm Wohl D et al, CROI 2015, Abstract 113LB

11 Week 48 : Laboratory AbnormaliDes E/C/F/TAF E/C/F/TDF Any grade 3 or 4 lab abnormalides CreaDnine kinase elevadon 7 6 LDL elevadon (fasdng) 5 2 Hypercholesterolemia (fasdng) 2 1 Hematuria 2 2 AST elevadon 2 2 Serum amylase elevadon 2 3 Neutropenia (<1000) 2 2 ALT elevadon 1 1

12 % Adverse Events (all grades) No significant differences E/C/F/TAF E/C/F/TDF Diarrhea Nausea Headache URI NasopharyngiDs 9 9 FaDgue 8 8 Cough 8 7 VomiDng 7 6 Arthralgia 7 5 Back pain 7 7 Insomnia 7 6 Rash 6 5 Pyrexia 5 5 Dizziness 5 4

13 Week 48 Safety Data Drug Levels Findings - 91% reducdon in TFV levels in plasma with TAF vs TDF Mean AUC 3410 (TDF) vs 297 (TAF) - 4x higher intracellular levels of TFV with TAF vs TDF Sax P et al, CROI 2015, Abstract 143LB

14 Week 48 Safety: Renal Endpoints No renal adverse events leading to discondnuadon with TAF: (n=4) with TDF vs 0 with TAF Proteinuria decreased with TAF :

15 Week 48 Safety: Bone Results No fragility fractures seen in the study Less effect on bone density by DEXA with TAF

16 Week 48 Safety: Lipid Results Lipids higher in TAF arm - TC:HDL rado not stadsdcally different

17 TAF Conclusions TAF non- inferior to TDF - 92% achieved virologic suppression - Low rates of virologic failure Favorable safety and tolerability - DisconDnuaDon due to AEs low - Common AEs similar in both arms - TAF smaller decreases in egfr - Significantly less proteinuria, albuminuria, and tubular proteinuria - Less impact on spine and hip bone mineral density Unanswered issues - Drug- drug interacdons - Role in HepaDDs B/C co- infected padents

18 HIV Cure

19 Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine Rarely, humans with chronic HIV infecdon will eventually produce andbodies that are potent and neutralize a broad range of HIV isolates InvesDgators asked if it was possible to use these already created andbodies to prevent HIV infecdon bypassing a tradidonal vaccinadon approach Johnson et al, CROI 2015, Abstract #66

20 Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine The Strategy 1. IdenDfy those rare HIV+ individuals who make broadly neutralizing andbodies 2. Isolate the andbody gene from their plasma cells 3. Clone it into a vector (AAV) Johnson et al, CROI 2015, Abstract #66 Inject into muscle Muscle cells make the broadly neutralizing andbody

21 Johnson et al, CROI 2015, Abstract #66 Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine First in mice Muscle cells stain ++ for the andbody (b12igg1) Muscle cells are andbody factories

22 Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine Then in monkeys 1. Monkeys immunized 2. Immunized and control animals challenged with SIV 3. All un- immunized monkeys became viremic and died 4. Immunized monkeys were protected AnDbody producdon condnues for > 6 years Johnson et al, CROI 2015, Abstract #66

23 Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine Planned in people Protocol A0003: Phase 1 study of raav- PG9DP in healthy adults Future studies using 3 rd and 4 th generadon broadly neutralizing and- HIV Abs and other and- infecdve molecules (e.g. IgG- CD4, Gardner, Nature, 2015; 519: 88-90) Johnson et al, CROI 2015, Abstract #66