1. N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 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 initial HIV-1 infection (Abstract # 113LB) - Renal and bone TAF vs tenofovir disoproxil fumarate (TDF) (Abstract # 143LB) Cure - Immunoprophylaxis by gene transfer (Abstract #66)

3. Tenofovir Alafenamide

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

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

6. Study Design Tx-Naïve Adults HIV-1 RNA > 1000 c/mL eGFR > 50 mL/min Tx-Naïve Adults HIV-1 RNA > 1000 c/mL eGFR > 50 mL/min E/C/F/TAF qday E/C/F/TDF qday (Stribild) 1:1 N=866 N=867 Week 04896144 Primary Endpoint Sax P et al, CROI 2015, Abstract 143LB Wohl D et al, CROI 2015, Abstract 113LB 2 phase 3 randomized, double-blind, double-dummy, active-controlled studies GS104 (N. America, EU, Asia); GS 111 (N. America, EU, Latin America) Primary endpoint – proportion with HIV-1 RNA < 50 c/mL Week 48 safety endpoints – serum creatinine, proteinuria, hip BMD, spine BMD

7. Baseline Characteristics Sax P et al, CROI 2015, Abstract 143LB ; Wohl D et al, CROI 2015, Abstract 113LB E/C/F/TAF E/C/F/TDF

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

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

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

11. Week 48 : Laboratory Abnormalities E/C/F/TAF E/C/F/TDF

12. % Adverse Events (all grades) No significant differences E/C/F/TAF E/C/F/TDF

13. Week 48 Safety Data Drug Levels Findings - 91% reduction 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 discontinuation with TAF: - 0.5 (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 ratio not statistically different

17. TAF Conclusions TAF non-inferior to TDF - 92% achieved virologic suppression - Low rates of virologic failure Favorable safety and tolerability - Discontinuation 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 interactions - Role in Hepatitis B/C co-infected patients

18. HIV Cure

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

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

21. Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine First in mice Muscle cells stain ++ for the antibody (b12IgG1) Muscle cells are antibody factories Johnson et al, CROI 2015, Abstract #66

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 Antibody production continues for > 6 years Johnson et al, CROI 2015, Abstract #66

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