ARV Update: 2016 and Beyond

6/6/2016

1

ARV Update: 2016 and Beyond

Antonio E. Urbina, MD

Associate Professor of Medicine

Icahn School of Medicine

Mount Sinai Hospital

Disclosures

• Scientific Advisory Panels: • Gilead, Thera‐technologies, Merck, VIIV

• Clinical Research: • BMS, VIIV

Overview

• ART has become simpler, safer and better tolerated– For last 19 months, no cases of MTCT in New York State

• The durability of the regimens has increased and virologicfailure with emergent resistance has become less common.

• Most patients with MDR‐HIV are currently suppressed on more complex, and perhaps fragile or cumbersome regimens. Therefore more new agents are still needed.

• For other patients adherence to oral ART presents a substantial challenge. Long‐acting agents, and new delivery systems for ART will be needed

Narrowing the Gap in Life Expectancy for HIV+ versus HIV‐ Subjects

Kaiser cohort data from 1996‐2011 evaluating life expectancy between HIV+ (n=25,768; 46% on ART at BL) and HIV‐ (n=257,600) subjects

• Mortality rate of 1,827 vs. 326 per 100,000 person‐years, respectively• Abridged life tables were used to estimate years of life remaining at age 20

Marcus J, et al, CROI 2016. Boston, MA. Oral 54

Even with early ART initiation, a life expectancy gap remains between HIV+ and HIV‐ subjects.

Mitigation of risk factors, like smoking, may further reduce the survival disparity.

Expected years of life remaining at age 20(95% confidence interval)

HIV+ HIV‐ Difference P value

Overall 49.3 62.3 13.1 (11.5‐14.6) <0.001

HIV+ and initiated ART with CD4 500

54.5 62.3 7.9 (5.1‐10.6) <0.001

+ No hepatitis B or C 55.4 62.6 7.2 (4.4‐10.0) <0.001

+ No drug/alcohol abuse 57.2 63.8 6.6 (3.9‐9.3) <0.001

+ No smoking 58.9 64.3 5.4 (2.2‐8.7) <0.001

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0.2 0.5 1.0 2.0 5.0 10

START Trial: Impact on Cancer• Results: Immediate vs. deferred ART initiation and the risk of any type cancer, infection‐related and

infection‐unrelated cancers in the START study

74% reduction in risk of infection related cancers (KS, HL & NHL,HPV)Factors associated with risk of Infection‐related cancers• Age• Baseline HIV‐RNA risk: • high income country

A: univariable, estimated in a Cox proportional hazards model with a single treatment indicator

B: adjusted for baseline covariates; age, gender, race, geographical region, smoking, BMI, hepatitis B/C, CD4 cell count and baseline log10 HIV RNA

C: adjusted for latest HIV RNA, modelled as <200 copies/mL vs HIV RNA >200 copies/mL

D: adjusted for latest CD4 cell count and latest HIV RNA (<200 copies/mL)

Model A

Model B

Model C

Model D

Model A

Model B

Model C

Model D

Model A

Model B

Model C

Model D

Any type cancer

(n=53)

Infection‐related cancer

(n=53)

Infection‐unrelated cancer

(n=53)

Borges A, et al. 23rd CROI; Boston, MA; February 22‐25, 2016. Abst. 160.

‐4

‐2

0

2

4

0 12 24 36 48 60

Change from Baseline

Months from Randomization

Current Health(Visual Analog Scale, 0‐100)

Immediate ART

Deferred ART

No of Participants:

Imm,: 2253 2150 1797 1038 559 146

Def.: 2287 2121 1773 1026 529 156

No of Participants:

Imm,: 2091 1977 1698 1014 555 145

Def.: 2119 1949 1677 993 521 153

‐4

‐2

0

2

4

0 12 24 36 48 60

Change from Baseline

Months from Randomization

General Health (SF‐12 v2, Scaled 0‐100)

Lifson A, et al. 23rd CROI; Boston, MA; February 22‐25, 2016. Abst. 475.

START Trial: Increased Quality of Life with Immediate ART Initiation

• Review of resistance testing results in British Columbia since 2009

• Significant decline in detected PI an RT resistance; despite increase in use of integrase inhibitors, rate of resistance remains very low

• Declining prevalence of drug resistant strains, and low prevalence of integrase inhibitor resistance, to date

BC Cohort: Trends in Drug Class Resistance in Recent Treatment Era

Lepik K, et al. 23rd CROI; Boston, MA; February 22‐25, 2016. Abst. 492LB.

331316

304 300 292 290 285

1.07 1.67 3.26 4.28 4.84 6.14 6.8

0

50

100

150

200

250

300

350

2009 2010 2011 2012 2013 2014 2015

HIV Drug resistan

ce/1000 ART‐Treated

Persons*

Year

Prevalence of Drug Resistance

RT, PI resistance/1000 ART‐treated

INI resistance/1000 ART‐treated

Decreasing prevalence of RT, PI resistance, trend p<0.001, R2 0.98

Increasing prevalence of INI resistance, trend p<0.001, R2 0.98

U.S. Clinics: Changes in Viral Load Over TimeCFAR Network of Integrated Clinical Systems (CNICS)

Cohort 29,467 Participants at 8 HIV Clinics

0102030405060708090100

1997 1999 2001 2003 2005 2007 2009 2011 2013

Calendar Year

Percentage of Suppressed Viral Load Over Time

30%

87%

OR Std Err 95% CI P‐value

Integrase Use 2.40 0.12 [2.17‐2.66] <0.01

Male 1.42 0.09 [1.23‐1.61] <0.01

Age (per year) 1.05 0.00 [1.04‐1.05] <0.01

Race (White=Ref)

Black 0.48 0.03 [0.43‐0.53] <0.01

Hispanic 1.09 0.08 [0.94‐1.26] 0.27

Other/Missing 1.24 0.14 [0.99‐1.55] 0.06

Years from Baseline 2.95 0.10 [2.76‐3.14] <0.01

Simoni J, et al. 23rd CROI; Boston, MA; February 22‐25, 2016. Abst. 1034.

Percent of Su

bjects

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Case # 1

• DG is a 47 year old WM, HIV+ (dx’d 2004), nadir CD4 count 400 with PMHx hypogonadism and hyperlipidemia. Patient is on emtricitabine/rilpivirine/TDF (Complera®) and reports excellent adherence. He presents to you on 4/2016 for HIV f/u after transferring care.

– Labs done that day reveal viral load of 9,026, + RPR 1:16 and testosterone >1200

– Repeat testing confirms elevated viral load and you perform a resistance test

Case # 1

• Given the results of the Genosure Prime, you decide to switch patient to:

– 1. emtricitabine/TDF (Truvada®) + DTG (Tivicay®)

– 2. emtricitabine/TDF (Truvada®) + darunavir/cobi (Prezcobix®)

– 3. abacavir/lamivudine/DTG (Triumeq®)

– 4. emtricitabine/elvitagravir/cobi/TAF (Genvoya®) + darunavir(Prezista®)

Case # 2

• TM is a 59 year old male with PMHx long standing HIV/AIDS, hyperlipidemia, GERD, BPH, osteoporosis, HTN on delavirdine, (Rescriptor®, 3 tabs twice daily), LPV/r (Kaletra®, 2 tabs twice daily) and raltegravir (Isentress®, 1 tab twice daily). He presents to you after transferring care and would like to discuss alternative ARV options.

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Genosure Archive

Case # 2

• Given the results of the Genosure Archive, you decide to switch the patient to:

– 1. DTG (Tivicay®) + rilpivirine (Edurant®)

– 2. DTG (Tivicay®) + darunavir/cobi (Prezcobix®)

– 3. emtricitabine/elvitagravir/cobi/TAF (Genvoya®) + darunavir(Prezista®)

– 4. DTG (Tivicay®) + darunavir/cobi (Prezcobix®) + etravirine(Intelence®)

Basics of ARV Management

Treatment Naive

• Perform genotyping on everyone prior to initiating ARVs– If patient in AHI or if you want to start

prior to results of resistance testing then:

• Use either DRV/r, DRV/c or DTG with TDF/FTC

Treatment Experienced

• Best to get resistance testing within 4 weeks of being on ARVs– Wild type virus can outgrow the minor

variants

• Familiarize yourself with the various resistant tests from Monogram– Genotypic testing +/‐ integrase

– Phenotypic +/‐ integrase

– Tropism

– Archive, genotypic testing

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Recommendations for Resistance Testing

DHHS Guidelines:

• Genotypic testing is recommended at baseline

• Genotypic testing is recommended at first and second failures in patients with suboptimal virologic response or virologic failure

• Addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drug‐resistance mutation patterns, particularly to protease inhibitors

• In persons failing integrase‐based regimens, genotypic testing for integrase resistance should be considered

• Trofile testing should be performed prior to use of entry inhibitor (maraviroc)

1718

Genotype or Phenotype or Both?

• Genotype can identify resistance when mutations are present only as mixtures, therefore can give an early warning sign that resistance is on the horizon

• Phenotype directly measures virus vs. drug– Is a true measure of susceptibility

• Both tests in combination may provide the most complete picture of resistance1

– This approach may be most useful in patients who are more treatment‐experienced

1Parkin, et al. JAIDS 31:128-136, 2002

Patient Case: History

• The patient is a 48‐year old man who has been HIV positive since the mid 1990s.

• He has been on multiple regimens over the years due to virologic breakthrough or adverse events.

• For the past several years, his virus has been well controlled.

• However, he recently failed his raltegravir containing regimen (RAL/TDF/FTC) with a viral load of 20,000+ copies/mL, which was confirmed on two separate samples.

GenoSURETM Integrase Results

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Genosure Archive

• Sequencing the integrated proviral HIV‐1 DNA present in infected cells of individuals with undetectable plasma HIV‐1 RNA levels can provide information about resistance‐associated mutations acquired in the past and archived in the HIV‐1 reservoir.

• Circulating peripheral blood mononuclear cells (PBMCs) are a source of cellular proviral DNA that can be used for genotyping to detect previously transmitted or emergent drug resistance mutations in virologically‐suppressed patients.

• Proviral DNA sequencing may be a valuable tool when used in combination with or in the absence of historical RNA genotype data to guide regimen switching in the setting of virologic suppression.

GenoSure ArchiveSM Process

3XHIV Pol

SCOPE Cohort

• UCSF well‐established cohort of HIV+ patients

• Patients for this study were selected using the following criteria:– Documented history of drug resistance

– Achieved durable virologic suppression

– PBMC aliquots available during a period of ART‐induced suppression

• Majority of these patients initiated ART prior to 2001

• PBMC samples from 48 patients were used in this study

• Cellular DNA was extracted from 4.5 million PBMC/sample for use in the GenoSure Archive assay

J. Toma1, et. al. Drug Resistance Profiles Derived from HIV‐1 DNA in ARV Suppressed Patients Correlate with Historical Resistance Profiles Obtained from HIV‐1 Plasma RNA

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SCOPE Cohort

*Demographic information was incomplete for one patient

Demographics N or Mean % or Range

Male 42 89%

Female 5 11%

Age 49 32‐73

CD4 Nadir 134 3‐361

CD4 at testing 686 371‐1232

Tx History

Years aviremic prior to testing 3.9 0.2‐13

Number of ARV regimens 5 2‐15

ART Resistance

NRTI Resistance 43 90%

NNRTI Resistance 24 50%

PI Resistance 32 67%

One Class Resistance 7 15%

Two class Resistance 16 33%

Three class Resistance 20 42%J. Toma1, et. al.

GenoSure Archive Demonstrates an 85% Sensitivity to Detect Major Resistance‐Associated Variants

All Variants NRTI NNRTI PI

Sensitivity 85% 89% 82% 77%

95% CI (80‐89%) (83‐94%) (67‐91%) (66‐85%)

False Neg. Rate 15% 11% 18% 23%

* * * ** * * *

Note: Low prevalence of resistance variants at some positions resulted in large confidence intervals*No variants present in the historical genotypes

ProteaseNNRTINRTI

J. Toma1, et. al.

GenoSure Archive Accurately Represents Historically Wildtype Variants

All Variants NRTI NNRTI PI

NPV 97% 96% 98% 96%

95% CI (95‐97%) (93‐97%) (96‐99%) (94‐98%)

False Omission Rate 3% 4% 2% 4%

ProteaseNRTI NNRTI

J. Toma1, et. al.

LYMPHOCYTETFV

OAT 1 & 3

RENAL TUBULAR CELL

TFV

PLASMA

91% LESSPLASMA TFV 1

TFV

TDF

TAF

TFV

GREATER PLASMA STABILITY

LESS PLASMA STABILITY

TFV

GI TRACT

RENAL TUBULAR CELL TFV

OAT 1 & 3

HIV

1. Sax P, et al. Lancet 2015OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.

Mechanism of ActionTenofovir Disoproxil Fumarate and Tenofovir Alafenamide

Wohl D, et al. CROI 2016. Boston, MA. #681

TAF 25 mg results in >90% lower TFV plasma levels

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Study Design

• Randomized, double‐blind, double‐dummy, active‐controlled study

SecondaryEndpoint

n=333

n=330

Primary EndpointHIV-1 RNA <50 c/mL

BL Wk 96Wk 48

F/TAF QD

F/TDF Placebo QD

Continue Third Agent

F/TDF QD

F/TAF Placebo QD

Continue Third Agent

Virologically Suppressed(< 50 c/mL) F/TDF + Third Agent eGFR ≥50 mL/min

Gallant J, et al. CROI 2016. Boston, MA. #29

F/TAF Dose: • 200/10 mg with boosted Pis• 200/25 mg with unboosted third agents

Efficacy at Week 48 (Snapshot)

F/TDF F/TAF

0

HIV

-1 R

NA

<50

c/m

L, %

‒10% +10%

5.1-2.5

1.3

Treatment Difference (95% CI)Virologic Outcome


Virologic Success

Virologic Failure

No Virologic Data

Changes in eGFR from Baseline

8.4 mL/min

2.8 mL/min

p <0.001

*eGFR calculated with Cockcroft‐Gault equation


Change in Renal Biomarkers at Week 48

AlbuminProtein β2MRBP

Urine Protein to Creatinine Ratio

Med

ian

% c

hang

e

RBP, retinol‐binding protein; β2M, β2‐microglobulin

Participants who remained on TDF continued to have increased proteinuria while those who switched to TAF had decreased proteinuria

All differences between treatments statistically significant (p <0.001)


F/TAF

F/TDF

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Change in Bone Mineral Density through Week 48

≥ 3% BMD increase at Week 48

F/TAF 30%p<0.001

17%p=0.003

F/TDF 14% 9%

321 310 300

320 310 306

321 309 300

317 305 303

F/TAF, n

F/TDF, n

Mea

n %

cha

nge

(95%

CI)

Spine

1.5

-0.2

1.1

-0.2

WeeksWeeks

p <0.001

Hip

p <0.001


Fasting Lipid Results

Total Cholesterol

LDL HDL Triglycerides TC: HDL Ratio

Med

ian

valu

e (m

g/dL

)

p <0.001

p <0.001

p=0.12

p=0.004

p=0.069

200

187183

182

128

112

115

110

52

495050

124

118112

112

3.7

3.6 3.63.6

F/TAF F/TDF

Patients initiating lipid-lowering agents 4% 4%

F/TAF F/TDF

Week 48

Baseline


Basics of ARV Management

New Agents

• TAF containing ARVs: – 1. elvitegravir/cobicistat/emtricitabine/

TAF (10 mg) [Genvoya®]

– 2. emtricitabine/rilpivirine/TAF 25 mg [Odefsey®]

– 3. emtricitabine/TAF (25 mg) [Descovy®]

• Cobicistat ARVs:– ATZ/cobi [Evotaz®]

– DAR/cobi [Prezcobix®]

Fine‐tuning experienced patients

• If possible, switch off all D drugs like stavudine and didanosine

• Consider switching off efavirenz‐containing regimes for CNS/psychiatric, lipo‐atrophic or elevated TGs

• Consider switching off older PIs like saquinavir, indinavir and LPV/r

Initial Regimens: Recommended

36January 2016

www.aidsetc.org

INSTI based DTG/ABC/3TC; only if HLA-B*5701 negative (AI)

DTG (QD) + TDF/FTC (AI)

EVG/COBI/TDF/FTC; only if pre-ART CrCl >70 mL/min (AI)

EVG/COBI/TAF/FTC; only if pre-ART CrCl ≥30 mL/min (AI)

RAL + TDF/FTC (AI)

PI based DRV/r (QD) + TDF/FTC (AI)

Note: 3TC can be used in place of FTC and vice versa; TDF: caution if renal insufficiency

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Initial Regimens: Alternative

37January 2016

www.aidsetc.org

NNRTI based EFV/TDF/FTC (BI)

RPV/TDF/FTC; only if pre-ART HIV RNA <100,000 copies/mL and CD4 >200 cells/µL (BI)

PI based ATV/c + TDF/FTC; only if pre-ART CrCl >70

mL/min (BI)

ATV/r + TDF/FTC (BI)

(DRV/c or DRV/r) + ABC/3TC; only if HLA-B*5701 negative (BIII for DRV/c, BII for DRV/r)

DRV/c + TDF/FTC; only if pre-ART CrCl >70 mL/min (BII)

Note: 3TC can be used in place of FTC and vice versa; TDF: caution if renal insufficiency

Initial Regimens: Other

38January 2016

www.aidsetc.org

INSTI based RAL + ABC/3TC; only if HLA-B*5701 negative (CII)

NNRTI based EFV + ABC/3TC; only if HLA-B*5701 negative and pre-ART HIV RNA <100,000 copies/mL (CI) a

PI based (ATV/c or ATV/r)b + ABC/3TC; only if HLA-B*5701 negative and pre-ART HIV RNA <100,000 copies/mL (CIII for ATV/c and CII for ATV/r)

LPV/r (QD or BID)c + ABC/3TC; only if HLA-B*5701 negative (CI)

LPV/r (QD or BID)c + TDF/FTC (CI)

Notes: 3TC can be used in place of FTC and vice versa

a. Consider alternative to EFV in women who plan to become pregnant or are not using effective contraception. b. ATV/r should not be used in patients who take >20 mg omeprazole per day.c. QD LPV/r is not recommended in pregnant women.

Initial Regimens: Other (2)

39January 2016

www.aidsetc.org

Other Regimens when TDF or ABC cannot be used

DRV/r + RAL; only if pre-ART HIV RNA <100,000 copies/mL and CD4 >200 cells/µL (CI)

LPV/r (BID) + 3TC (BID) (C1) Novel ARV Studies

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GARDEL: Dual ART With LPV/RTV + 3TC vs Triple ART With LPV/RTV + 2 NRTIs

• Randomized, open-label phase III noninferiority trial– Primary endpoint: HIV-1 RNA < 50 c/mL (ITT-e, FDA snapshot analysis)

• Pts with virologic response at Wk 48 offered extension to Wk 96

ART-naive pats with HIV-1 RNA > 1000 copies/mL; no NRTI/PI resistance;

HBsAg negative(N = 426)

Lopinavir/Ritonavir 400/100 mg BID +Lamivudine 150 mg BID

(n = 217)

Lopinavir/Ritonavir 400/100 mg BID +Investigator‐Selected NRTIs in FDC*

(n = 209)

Wk 48primary analysis

Stratified by HIV‐1 RNA (≤ vs > 100,000 c/mL)

Wk 24interim analysis

Cahn P, et al. EACS 2015. Abstract 961.

*ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%

Wk 96 extension analysis

GARDEL: Dual ART Noninferior to Triple ART at Wk 48 and Wk 96

• Safety and tolerability also similar between treatment arms

Virologic Success

Virologic Nonresponse

D/C due to AE or Death

D/C for Other Reasons

Cahn P, et al. EACS 2015. Abstract 961. Cahn P, et al. Lancet Infect Dis. 2014;14:572-580.

Wk 48 difference: +4.6% (95% CI: -2.2 to 11.8; P = .171)

Wk 96 difference: +5.9% (95% CI: -2.3 to 14.1; P = .165)

100

80

60

40

20

0

Pts

(%

)

Dual ART

Triple ART

4.7 5.91.4

5.4 6.1 7.92.4 2.1 0.6

2.86.6 10.6

88.383.7

90.384.4

Wk: 9648 9648 9648 9648

ATLAS-M: Switch From Suppressive ATV/RTV + 2 NRTIs to ATV/RTV + 3TC

• Randomized, multicenter, open-label phase IV trial– Primary endpoint: absence of treatment failure at Wk 48, defined as ART

modification for any reason and/or virologic failure

Pts receiving stable ATV/RTV + 2 NRTIs

(≥ 3 mos) with HIV-1 RNA < 50 c/mL and CD4+

> 200 cells/mm3

(≥ 6 mos), and no previous virologic failure

(N = 266)

Switch to ATV/RTV 300/100 mg + 3TC 300 mg QD(n = 133)

Continue ATV/RTV 300/100 mg QD + 2 NRTIs(n = 133)

Wk 48

primary endpoint

Wk 24interim analysis

Wk 96

planned follow‐up

Di Giambenedetto S, et al. EACS 2015. Abstract 867.

ATLAS-M: Virologic Efficacy and Safety Through Wk 48

• Switch to ATV/RTV + 3TC noninferior and superior (post hoc) to continuing ATV/RTV + 2 NRTIs in ITT, S=F analysis

• Significantly greater increases in TC (P < .01), LDL (P < .05), and HDL (P < .01) with ATV/RTV + 3TC vs ATV/RTV + 2 NRTIs at Wk 48

• Mean change in eGFR at Wk 48: +2 mL/min with ATV/RTV + 3TC vs -4 mL/min with ATV/RTV + 2 NRTIs (P < .001)

Di Giambenedetto S, et al. EACS 2015. Abstract 867.

1.2 18.4

9.8

ATV/RTV + 2 NRTIs

ATV/RTV + 3TC

-12 0 12

Treatment Difference (95% CI)100

80

60

40

20

0

Pts

Fre

e o

f Tr

eatm

ent

Fai

lure

(%

)

BL W4 W12 W24 W36 W48

ATV/RTV + 3TC ATV/RTV + 2NRTIs99.2 100 97.7 94 94.7 91 91.7

85.7 89.583.5

89.5

79.7

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Open‐label, single‐arm phase IV exploratory trial

– Primary endpoint: HIV‐1 RNA < 50 copies/mL at Wk 48 (ITT‐e, FDA snapshot analysis)

PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts

Figueroa MI, et al. EACS 2015. Abstract 1066.

Treatment-naive ptswith HIV-1 RNA

5000-100,000 copies/mL; CD4+ cell count ≥ 200 cells/mm3;HBsAg negative

(N = 20)

Second Cohort

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

First Cohort

Second cohort to be enrolled following confirmation of

first cohort success at Wk 8

PADDLE: All Pts VirologicallySuppressed by Wk 8 of DTV + 3TC

• Included 4 pts with HIV-1 RNA > 100,000 copies/mL at BL

Figueroa MI, et al. EACS 2015. Abstract 1066. .

Pt #HIV-1 RNA, copies/mL

Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 241 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50

2 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

3 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 50

4 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 50

5 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50

6 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

7 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

8 25,071 24,368 6264 1377 Not done 268 105 < 50 < 50 < 50 < 50 < 50 < 50

9 14,707 10,832 Not done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

11 50,089 273,676 160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 50

12 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 50

13 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 50

14 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 50

15 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50 Not done < 50 < 50 < 50

16 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

17 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 50

18 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 50

19 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 50

20 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

‐3

‐2.8

‐2.6

‐2.4

‐2.2

‐2

0 2 4 8 12 24

Change

in Viral Load from baseline (Log10)

Week

PADDLE

SPRING

SINGLE

‐3

‐2.8

‐2.6

‐2.4

‐2.2

‐2

0 2 4 8 12 24

Change

in Viral Load from baseline (Log10)

Week

PADDLE

SPRING‐1

SINGLE

pVL change at each time point (Mean ±Standard error of the mean)

0.0 0.0

Sued O, et al. 23rd CROI; Boston, MA; February 22‐25, 2016. Abst. 947.

Cross Study PK Comparison: Comparable Viral Decay in Dual and Triple Dolutegravir‐based ART

pVL Change at Each Timepoint(Mean=standard Error of the Mean)

pVL Change at Each Timepoint(Mean=standard Error of the Mean),

Normalized per Baseline pVL

Simplification from a Complex DRV‐Based MTR to 2‐Tab E/C/F/TAF + DRV

Treatment Naïve PatientsStudy 102 and 103

Phase 3, multi-centered, randomized, open label, active-controlled

HIV SuppressedDRV-Based MTR

eGFR ≥50 mL/min

Primary EndpointEfficacy of simplification to E/C/F/TAF + DRV vs continuation of a complex DRV-based MTR

by FDA Snapshot analysis (HIV-1 RNA < 50 copies/mL at Week 24)

Secondary EndpointsIntensive PK in a subset of subjectsEfficacy by HIV-1 RNA <50 or <20 copies/mL at Week 48Safety and tolerability through Week 48

Resistance on historical genotype• ≥2 class resistance• No Q151M, T69ins in RT, signature DRV‐R or INSTI‐R• Permissive: M184V/I, K65R, ≤3 TAMs

ClinicalTrials.gov Identifier: NCT01968551

Switch to E/C/F/TAF + DRV QD

Continue DRV-Based MTR

Primary Endpoint

Week 24 Week 144

2:1

N=89

N=46

Key inclusion criteria• HIV‐1 RNA <50 c/mL for ≥4 months• No HBV infection

Huhn G, et al. ID Week 2015. San Diego, CA. Oral #726

Week 48

DRV dose: 800 mg once daily

48

6/6/2016

13

Baseline CharacteristicsE/C/F/TAF + DRV, n=89 DRV MTR, n=46

Median age, years 49 47

Male 82% 61%

Black or African descent 39% 57%

Median CD4 count, cells/μL 519 518

Median eGFRCG, mL/min 99 100

Hyperlipidemia / HTN / DM / CVD 46% / 34% / 8% / 7% 28% / 37% / 11% / 4%

Prior ARV regimens

Median number pills per day 5 5

≥6 pills per day 40% 37%

Regimen with at least BID dosing 65% 65%

TDF / ABC / other NRTIs 61% / 11% / 12% 54% / 11% / 13%

RAL 56% 50%

Resistance

2‐class / 3‐class resistance 70% / 26% 74% / 20%

M184V/I 85% 78%

K65R 20% 30%

NNRTI‐R / PI‐R 89% / 38% 87% / 28%

49Huhn G, et al. ID Week 2015. San Diego, CA. Oral #726

MTR=multiple tablet regimen

Mea

n (9

5%C

I) C

once

ntra

tion

[ng/

mL]

Intensive PK Sub‐StudyPharmacokinetics of EVG, DRV, TAF, and TFV

• EVG Ctrough >10‐fold above protein binding adjusted IC95 (45 ng/mL)

• DRV Ctrough >22‐fold above protein binding adjusted IC50 (55 ng/mL)

• TAF exposures in efficacious range demonstrated in E/C/F/TAF Studies 104+111

• TFV exposure (mean [%CV] AUC: 367 [33] ng*h/mL) well below levels observed following TDF‐containing regimens

EVG Concentration

IC95 (45 ng/mL) IC50 (55 ng/mL)

Time (h)

DRV Concentration

Time (h)

E/C/F/TAF + DRV

E/C/F/TAF + DRV

COBI adequately boosted EVG and DRV, providing exposures established for efficacy


MTR=multiple tablet regimen

Virologic Outcomes at Week 24 and 48

51

E/C/F/TAF + DRV was statistically superior to DRV-based MTRs at Week 48

Virologic Success(HIV-1 RNA < 50)

Virologic Failure No Virologic Data

W24 W48 W24 W48 W24 W48

Su

bje

cts

(%)

E/C/F/TAF + DRV (n=89)

DRV MTR (n=46)DRV MTR E/C/F/TAF + DRV

Treatment Difference (95% Confidence Interval)

18.3

33.0

Week 24

Week 48 3.5

p=0.23

p=0.004

- At Week 48, significantly higher virologic success rate at the more stringent cutoff (HIV-1 RNA <20 copies/mL) with E/C/F/TAF + DRV compared with DRV MTR (90% vs 72%, p=0.012).- Emergent resistance through Week 48: 0 E/C/F/TAF + DRV vs 1 DRV MTR (M184V/I + K65R).- Discontinued due to other reasons: E/C/F/TAF + DRV (1 investigator’s discretion, 1 withdrew consent) vs DRV MTR (3 withdrew consent, 2 lost to follow-up).


Treatment Satisfaction Scores at Weeks 24 and 48

52

Patient Reported Outcomes: HIV Treatment Satisfaction (HIV-TSQ) Questionnaire

Mean change

Mean Baseline HIV-TSQ Score*

Worsening Improvement

p <0.001†Week 24

Week 48 p <0.001†

E/C/F/TAF + DRV

DRV MTR

*ANCOVA HIV-TSQ at baseline 0‒6 response range, n=10 questions, higher score=better satisfaction in recent weeks; HIV-TSQ (change) post-baseline: -3‒3 response range, higher=better satisfaction; †From ANCOVA model (treatment as fixed effect; baseline total HIV-TSQ score as covariate).

Simplification to 2-tablet E/C/F/TAF + DRV was associated with more treatment satisfaction at Weeks 24 and 48 than DRV + MTR


6/6/2016

14

Conclusions

• Simplification from ~5 pills to 2 pills per day regimen of E/C/F/TAF + DRV resulted in:

– Statistically superior rates (94% vs 76%) of HIV suppression at Week 48

– Appropriate COBI‐boosting of EVG and DRV based on exposures established for efficacy

• The 2‐tablet E/C/F/TAF + DRV regimen was safe and well tolerated

– Significant declines in proteinuria and tubular proteinuria; stable eGFR

– More treatment satisfaction at Weeks 24 and 48

• Virologically suppressed adults on complex DRV‐based MTRs with 2 and 3‐class MDR HIV including M184V/I and K65R in RT may benefit from regimen simplification to E/C/F/TAF +DRV


FTC/TAF PrEP Protects Macaques from Rectal SHIV Infection

FTC/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with FTC/TDF but with a substantially reduced TFV dose1

– FTC/TAF protected 100% of macaques (N=6) challenged with SHIV in a similar, pre‐clinical trial2

1. Massud I, et al. CROI 2016. Boston, MA. #1072. HeneineW, et al. CROI 2006. Denver, CO. #32LB

SHIV challenges (weeks, n)

Per

cent

pro

tect

ed

0

20

40

60

80

100

Placebo FTC/TAF

1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 17 18 19

100%

0%

SHIV challenge repeated weekly for up to 19 weeks

FTC/TAF

PBO

‐24h SHIV +2h

‐24h SHIV +2h

Treatment arm(n=6)

Placebo arm(n=6)

FTC/TAF should not be used for PrEP in humans until a planned clinical study is completed

CDC Proof of Concept Study: FTC/TAF for PrEP

HIV‐1 Life Cycle

Budding

Assembly/cleavage

Release

Maturationinhibitor

Maturation

Lataillade et al. CROI 2015, Abstract 114LB.

ARV Update: 2016 and Beyond

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