NORTHWEST AIDS EDUCATION AND TRAINING CENTER

CROI 2015: Treatment and Cure Highlights

Shireesha Dhanireddy

Robert Harrington

March 17, 2014No financial conflicts of interest

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)

Tenofovir Alafenamide

TAF vs TDF:

Sax P et al, CROI 2015, Abstract 143LB

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

Study Design

Tx-Naïve AdultsHIV-1 RNA > 1000 c/mLeGFR > 50 mL/min

E/C/F/TAF qday

E/C/F/TDF qday (Stribild)

1:1

N=866

N=867

Week 0 48 96 144

Primary Endpoint

Sax P et al, CROI 2015, Abstract 143LBWohl 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

Baseline Characteristics

Sax P et al, CROI 2015, Abstract 143LB ; Wohl D et al, CROI 2015, Abstract 113LB

Median age, year 33 35

Sex, %

Male 85 85

Female 15 15

Race/ethnicity, %

Black or African 26 25

Hispanic 19 19

Median VL, log 4.58 4.58

% with VL >100K 23 23

Median CD4 count 404 406

% with CD4 count < 200 13 14

Median eGFR 117 114

% with Proteinuria (any grade) 10 10

E/C/F/TAF E/C/F/TDF

TAF vs TDF

Screened (n=2175)

TAF Arm(n=866)

TDF arm (n=867)

95% on treatment(n=821)

92% on treatment(n=796)

Sax P et al, CROI 2015, Abstract 143LB ; Wohl D et al, CROI 2015, Abstract 113LB

At 48 weeks

Week 48 Efficacy Data

Wohl D et al, CROI 2015, Abstract 113LB

TAF is non-inferior to TDF

Week 48 Efficacy Data

Wohl D et al, CROI 2015, Abstract 113LB

• Significantly greater increase in CD4 count in TAF arm

Week 48 : Laboratory Abnormalities

Any grade 3 or 4 lab abnormalities 20 20

Creatinine kinase elevation 7 6

LDL elevation (fasting) 5 2

Hypercholesterolemia (fasting) 2 1

Hematuria 2 2

AST elevation 2 2

Serum amylase elevation 2 3

Neutropenia (<1000) 2 2

ALT elevation 1 1

E/C/F/TAF E/C/F/TDF

% Adverse Events (all grades)No significant differences

Diarrhea 17 19

Nausea 15 17

Headache 14 13

URI 11 13

Nasopharyngitis 9 9

Fatigue 8 8

Cough 8 7

Vomiting 7 6

Arthralgia 7 5

Back pain 7 7

Insomnia 7 6

Rash 6 5

Pyrexia 5 5

Dizziness 5 4

E/C/F/TAF E/C/F/TDF

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

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 :

Week 48 Safety: Bone Results

• No fragility fractures seen in the study• Less effect on bone density by DEXA with TAF

Week 48 Safety: Lipid Results

• Lipids higher in TAF arm- TC:HDL ratio not statistically different

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

HIV Cure

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

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 cells3. Clone it into a vector (AAV)

Inject into muscle Muscle cells make the broadly neutralizingantibody

Johnson et al, CROI 2015, Abstract #66

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

Immunoprophylaxis By Gene Transfer:Shortcut To An HIV Vaccine

Then in monkeys

1. Monkeys immunized2. Immunized and control animals challenged with SIV3. All un-immunized monkeys became viremic and died4. Immunized monkeys wereprotected

Antibody production continues for > 6 years

Johnson et al, CROI 2015, Abstract #66

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 3rd and 4th generation broadly neutralizing anti-HIV Abs and other anti-infective molecules (e.g. IgG-CD4, Gardner, Nature, 2015; 519: 88-90)

Planned in people