5/10/2017

1

Joel Gallant, MD, MPH

Southwest CARE CenterSanta Fe, NM

Johns Hopkins University School of MedicineUniversity of New Mexico School of Medicine

HIV Treatment Update

Disclosures

Consulting, Advisory Boards, and DSMBs

Bristol-Myers Squibb

Gilead Sciences

Merck & Co.

Theratechnologies

ViiV Healthcare/GSK

Research Support

AbbVie

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Merck & Co.

Sangamo BioSciences

ViiV Healthcare/GSK

5/10/2017

2

DHHS Guidelines, July 2016: What to Start

Recommended regimens

PI based DRV/r + (TDF/FTC or TAF/FTC)

INSTI based DTG + (TDF/FTC or TAF/FTC) DTG/ABC/3TC EVG/c/TDF/FTC or EVG/c/TAF/FTC RAL + (TDF/FTC or TAF/FTC)

Alternative regimens

NNRTI based EFV/TDF/FTC or EFV + TAF/FTC RPV/TDF/FTC or RPV/TAF/FTC (VL <100,000; CD4 >200)

PI based (ATV/c or ATV/r) + (TDF/FTC or TAF/FTC) (DRV/c or DRV/r) + ABC/3TC DRV/c + (TDF/FTC or TAF/FTC)

DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, July 2016.

IAS–USA Guidelines, July 2016:What to Start

Günthard HF, et al. JAMA 2016;316:191-210.

Recommended Regimens

DTG/ABC/3TCDTG + FTC/TAFEVG/c/FTC/TAFRAL + FTC/TAF

Regimens When INSTIs are Not an Option

DRV/c or DRV/r + (FTC/TAF, FTC/TDF or ABC/3TC)EFV/FTC/TDFRPV/FTC/(TAF or TDF)

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3

LYMPHOCYTE

TFV

TFV

RENAL TUBULAR

CELL

RENAL TUBULAR

CELL

91% lower plasma TFV

HIV

PLASMAGI

TRACT

TDF(tenofovirdisoproxilfumarate)

300 mg

TAF(tenofovir

alafenamide)

25 mg

TAF vs. TDF: Mechanism of Action

1. Lee W et al. Antimicr Agents Chemo 2005;49:1898-906; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51:543-50;3. Babusis D, et al. Mol Pharm 2013;10:459-66; 4. Ruane P, et al. JAIDS 2013;63:449-5; 5. Sax P, et al. JAIDS 2014;67:52-8; 6. Sax P, et al. Lancet 2015;385:2606-15.

GS 104/111: Initial ART with E/C/F/TAF v. E/C/F/TDF

Parallel, randomized, double-blind, active-controlled phase III studies

– 1o endpoint: VL < 50 at Wk 48 (FDA Snapshot)

Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615.

EVG/COBI/FTC/TAF(n = 866)

EVG/COBI/FTC/TDF(n = 867)

ART-naïve pts withVL ≥ 1000,

eGFR ≥ 50 mL/min(N = 1733)

Stratified by VL, CD4 count, geographic region

Wk 48Primary endpoint Wk 144

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4

Initial ART with E/C/F/TAF v. E/C/F/TDF:144 Week Efficacy

0

10

20

30

40

50

60

70

80

90

100

48 96 144 48 96 144 48 96 144

Treatment DifferenceWk 48: 2.0% (95% CI: -0.7% to 4.7%)

Wk 144: 4.2% (95% CI: 0.6% to 7.8%; P = .02)

E/C/F/TAF (N=886) E/C/F/TDF (N=867)

Virologic success Virologic Failure No data

Efficacy similar across subgroups, trending toward or significantly better with TAF in each group

– By baseline VL, baseline CD4, adherence, age, sex, race, region

Virologic failure with resistance by Wk 144: 1.4% in each arm

Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615.

Initial ART With E/C/F/TAF vs E/C/F/TDF:144 Week Safety Outcomes

More discontinuation for AEs with TDF vs TAF

– 3.3% vs 1.3% (P = .01)

Greater spine and hip BMD loss with TDF vs TAF

– 6 D/C’s for bone AEs in TDF arm vs 0 in TAF arm

TC, LDL, and HDL increases greater with TAF vs TDF

– Rates of lipid-modifying therapy initiation similar: 5.5% vs 5.8%

Med. eGFR increase lower with TAF vs TDF regimen: 1.6 vs 7.7 mL/min (P < .001)

Arribas JR, et al. CROI 2017. Abstract 453.

Renal Events Leading to Discontinuation, n

TAF(n = 866)

TDF(n = 867)

Proximal renal tubulopathy

0 4

Cr elevation or eGFR decrease

0 3

Renal failure 0 2

Nephropathy 0 1

Proteinuria 0 1

Bladder spasm 0 1

Total 0 12

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5

CD4 CountVL

ARIA: DTG/ABC/3TC vs. ATV/r + FTC/TDF in ART-Naive Women at Wk 48

Orrell C, et al. AIDS 2016. Abstract THAB0205LB. Johnson M, et al. HIV Glasgow 2016. Abstract P035. Hagins D, et al. IDWeek 2016. Abstract 949.

Outcome, % (n)DTG/ABC/3TC

(n = 248)ATV/r + FTC/TDF

(n = 247)Virologic nonresponse 6 (16) 14 (35)

No virologic data 12 (29) 15 (36)

0 4 8 12 16

3.1

10.5

17.8

FavorsDTG/ABC/3TC

Favors ATV/r +FTC/TDF

Overall Treatment Difference (95% CI)

20-16 -12 -8 -4

P = .005

DTG/ABC/3TC

VL

< 5

0 (%

)

Overall ≤ 100K > 100K ≤ 350 > 350

100

80

60

40

20

0

82

71

8374

80

64

85

7278

71

203/248

176/247

148/179

134/181

55/69

42/66

111/130

89/124

92/118

87/123

ATV/r + FTC/TDF

n/N =

Virologic Outcome

WAVES: Switch to E/C/F/TAF in Women at Wk 48

Open-label extension study

Hodder S, et al. CROI 2017. Abstract 443.

Virologic Outcome Treatment Difference(95% CI)

VL

< 5

0 (%

)

100

80

60

40

20

0

Switch to EVG/c/FTC/TAF (n = 159)

Continue ATV/r+FTC/TAF (n = 53)

Success Failure No Data

n= 150 46 3 2 6 5

9487

2 4 49

0 10 20

-20 -10

-1.2

7.5

19.4

FavorsE/c/F/TAF

Favors ATV/r+ FTC/TAF

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6

Integrase resistance in the U.S.

Transmitted INSTI resistance remains rare; rates of on-treatment INSTI resistance remains low[1-3]

CDC National HIV Surveillance System[1]:

– Prevalence of INSTI resistance through 2014: 65/14,468 (0.4%)

– Pre-ART prevalence of INSTI resistance (ie, transmitted): 2/4631 (0.04%)

UNC CFAR HIV Clinical Cohort[2]:

– 2015 INSTI resistance prevalence in 685 pts who began ART in 2007 or later: 1%

Modeling: assuming 0.1% rate of transmitted INSTI resistance and $250 cost per test: pre-ART INSTI resistance testing correlated with worse outcomes, higher costs vs no test[3]

1. Hernandez AL, et al. CROI 2017. Abstract 478. 2. Davy T, et al. CROI 2017. Abstract 483. 3. Koullias Y, et al. CROI 2017. Abstract 493.

Emergence of INSTI Resistance in Acute Infection Treated With DTG + FTC/TDF

45-yo man with PCP and ARS

Started DTG + FTC/TDF and discharged; readmitted to ICU several days later for hypoxia

VL increased after readmission despite adherence (including DOT in hospital); no divalent cation use

– DRV/r added, VL decreased

– Pneumonia improved; pt discharged

Rapid INSTI emergence by deep seq: eg, Q148K population increased from 0.0015% at Timepoint 1 to 20.9% at Timepoint 3

Fulcher JA, et al. CROI 2017. Abstract 500LB.

Days

0

200

400

600

800

1000

101

102

103

104

105

106

107

0 20 40 60 80 100

VL

(c

/mL

)

CD

4+

Co

un

t (cells/m

m3)

Initiated DTG/FTC/TDF; GT (clinical assay): RT: V118I, F214L; IN: Not Tested

Added DRV/RTV; GT (clinical assay): RT: M184V, V118I, F214L; IN: G163E

Time Points of IN Deep sequencing

1

23

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7

D:A:D: Exposure to ATV/r or DRV/r and Risk of CVD

Prospective analysis of pts followed from 1/1/09 (BL) to earliest CVD, last visit + 6 mos, or 2/1/16 (N = 35,711)– 1157 (3.2%) developed CVD

(MI, CVA, sudden cardiac death, invasive CV procedure)

Cumulative expos. to DRV/r, but not ATV/r, assoc. with increased CVD risk in multivariate analysis: 59% risk increase per 5-yrs’ DRV/r– Not mediated by dyslipidemia,

in contrast with 1st-generation PIs

Ryom L, et al. CROI 2017. Abstract 128LB.

CVD Risk per 5 Yrs of ARV Exposure, IRR (95% CI)

Model ATV/r DRV/r

Univariate1.25 (1.10-

1.43)1.93 (1.63-

2.28)

Multivariate

Baseline adjusted*

1.03 (0.90-1.18)

1.59 (1.33-1.91)

Time-updated adjusted*

1.01 (0.88-1.16)

1.53 (1.28-1.84)

*Adjusted for: BMI, CKD, DM, CD4, dyslipidemia.

Limitations: potential for unmeasured confounding; observational study; unable to distinguish between DRV/r800/100 mg QD vs DRV/r 600/100 mg BID

Initial Therapy:My choices for specific clinical scenarios

Scenario Regimens

Desires single-tablet regimen (STR) DTG/ABC/3TC EVG/c/FTC/TAF

STR doesn’t matter DTG + FTC/TAF

HBV Coinfection FTC/TAF-based regimen

Starting without resistance test results (DRV/c or DTG) + FTC/TAF

Desire for pregnancy RAL + (FTC/TDF or ABC/3TC) DRV/r + (FTC/TDF or ABC/3TC)

Questionable adherence DTG/ABC/3TC DRV/c + FTC/TAF

Tuberculosis EFV/FTC/TDF RAL 800 mg bid + (FTC/TDF or ABC/3TC)

Drug interactions (including HCV) DTG or RAL-based regimen

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8

When to Start?: Guidelines

Symptoms CD4 <200

CD4 200-350

CD4 350-500

CD4 >500

US DHHS YES YES YES YES YES

IAS-USA YES YES YES YES YES

EACS YES YES YES YES YES

BHIVA (UK) YES YES YES YES YES

WHO YES YES YES YES YES

T.F.

• 28-year-old gay man presents with 3 days of fever, night sweats, lymphadenopathy, and sore throat. A rapid 4th

generation HIV test is positive

• Tested negative 6 months ago. Has been having condomless sex with multiple partners. He asked his primary care provider about PrEP and was told he would have to see “a specialist.”

• Otherwise in good health. Has well controlled depression on citalopram. He has been vaccinated against hepatitis B.

• Sees a nurse and case manager the day after diagnosis, and baseline lab tests are drawn. Has appointment with HIV provider in 10 days. Wants to start ART as soon as possible

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9

T.F.

When would you start ART?

1. After he keeps several clinic appointments (~3 months)

2. After baseline genotype results are available (~2-3 weeks)

3. At the HIV provider visit (10 days)

4. If creatinine is normal and HBsAg is negative (1-2 days)

5. Today

RAPID Start: Time to VL suppression by ART initiation strategy: SFGH 2006-2014

RAPID

RAPID vs. universal ART p<0.001

Universal ART

CD4-guided ART

Pro

po

rtio

n

<20

0 c/

mL N = 39

Pilcher CD, et al. J Acquir Immune Defic Syndr 2016

5/10/2017

10

Rapid Start:Potential regimens

Regimens to consider

DTG + FTC/TAF

EVG/c/FTC/TAF

DRV/c + FTC/TAF

Drugs to avoid

ABC (need HLA B*5701)

TDF (need eGFR)

RPV (need VL, CD4)

EFV, NVP (need genotype)

Switching Therapy

5/10/2017

11

Summary of TAF Switch Studies in Virologically Suppressed Patients

Trials:

GS-109: TDF-containing regimens to EVG/COBI/FTC/TAF

GS -112: Switch to EVG/COBI/FTC/TAF in patients with impaired renal function

GS-119: ART + DRV/r to EVG/COBI/FTC/TAF + DRV in ART-experienced patients

GS-1089: FTC/TDF to FTC/TAF

GS-1160: EFV/FTC/TDF to RPV/FTC/TAF

GS-1216: RPV/FTC/TDF to RPV/FTC/TAF

Results:

Noninferiority, with superiority in GS-109 (switch from EFV/FTC/TDF or ATV/r + FTC/TDF) and superiority in GS-119

Increase in bone density

Stability of eGFR (increase in GS-1089 and GS-112) with no tubular toxicity and decrease in overall and tubular proteinuria

.

-2.5 5.1

1.3

-5.3

-0.5

4.4

-10 0 10

GS 1089: Switch from F/TDF to F/TAFWeeks 48 and 96 Efficacy

FTC/TAF noninferior to FTC/TDF at Weeks 48 and 96

Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125

FTC/TDF FTC/TAF

Pat

ient

s, %

94

05

93

26

89

29

89

1

10

0

20

40

60

80

100

Treatment Difference (95% CI)Virologic Outcome

48 48 4896 96 96Week

Wk 48

Wk 96

Success(< 50 copies/mL)

Failure No Virologic Data

FTC/TAF (n=333) FTC/TDF (n=330)

5/10/2017

12

-26

3

-4

-30

3

27

43 47

-50

-25

0

25

50

GS 1089: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Weeks 48 and 96

All differences between treatments statistically significant (p <0.001)

Med

ian

% C

hang

e

UrineAlbumin:Cr

Urine Protein:Cr

Urineβ2M:Cr

UrineRBP:Cr

10 4

-20

-10

0

10

20

Med

ian

Cha

nge,

mL/

min

eGFR

FTC/TAF FTC/TDF

Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125

GS 1089: Switch from F/TDF to F/TAF: Bone density changes through Week 96

321 310 300

320 310 306

294

297

287

292

321 309 300

317 305 303

293

296

288

289

FTC/TAF

FTC/TDF

n

Mea

n %

Cha

nge

(95%

CI)

Spine

WeekWeek

2.2

-0.2

p <0.001

Hip

1.9

-0.3

p <0.001

1.7

-0.1

1.2

-0.1

FTC/TAF FTC/TDF p value FTC/TAF FTC/TDF p value

≥ 3% increase 40% 18% < 0.001 29% 11% < 0.001

≥ 3% decrease 8% 19% < 0.001 6% 15% < 0.001

Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125

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13

TDF to TAF switch

Advantages:

Increased eGFR

Decreased proteinuria

Improved bone density

Smaller pill size

Disadvantages:

Loss of TDF lipid effect

TAF will be more expensive than generic TDF

Günthard HF, et al. JAMA 2016;316:191-210.

IAS-USA recommendations: “If there is no increase in the price of TAF vs. that of TDF, switching from TDF to

TAF is reasonable even if patients are not experiencing TDF-related toxic effects.”

Alternative StrategiesUsing Approved Drugs

5/10/2017

14

SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV

Open-label, multicenter phase III trials of pts with virologic suppression (N=1024) randomized to continue baseline ART vs switch to DTG + RPV

1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E

– Documented nonadherence at VF

– Resuppressed with continued DTG + RPV

– No INSTI resistanceLlibre JM, et al. CROI 2017. Abstract 44LB.

Virologic Nonresponse

HIV-1 RNA< 50 c/mL

No Data

100

80

60

40

20

0

Pts

(%

)

95 95

< 1 15 4

Treatment difference: -0.2% (95% CI: -3.0% to 2.5%)

DTG + RPV (n=513)Baseline ART (n=511)

SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV: Safety Outcomes

AE rates generally similar between arms through Wk52– Numerically higher rate of

drug-related grade 1/2 AEs with switch: 17% vs 2%

– Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%

No notable change in lipids through Wk 48 in either treatment arm

Llibre JM, et al. CROI 2017. Abstract 44LB.

Bone-specificalkaline

phosphatase

Osteocalcin Procollagen 1N-terminal propeptide

Bone Turnover Markers

DTG + RPV Baseline ART

0

20

60

40

80

Me

an

(µ

g/L

)

BaselineWk 48

15.912.9

100 BaselineWk 48

16.2 17.123.8

19.024.0 23.1

53.0

45.6

55.3 54.7

P < .001P < .001

P < .001

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15

PADDLE: Dolutegravir + Lamivudine for Treatment-Naive Pts

Cahn P, et al. AIDS 2016. Abstract FRAB0104LB.

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 24 Wk 36 Wk 48

1 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ANRS 167 LAMIDOL: Switch to DTG + 3TC in Suppressed Pts

Noncomparative, open-label, single-arm multicenter trial

1o endpoint: therapeutic success at Wk 56 (ie, after 48 wks of dual therapy)

Therapeutic failure: VL > 50 interruption, lost to f/u, death

Joly V, et al. CROI 2017. Abstract 458.

DTG + 2 NRTI†

VL ≤ 50 x ≥ 2 yrson 1st-line ART;

≤ 2 ART modifications, except within 6 mosof study start; CD4

> 200 (N = 110)

Wk 8* Wk 56

*Pts with VL ≤ 50 proceeded to phase II. †In phase I, third agent in regimen replaced with DTG; baseline NRTI backbone maintained.

DTG + 3TC(n = 104)

Phase I Phase II

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ANRS 167 LAMIDOL: Switch to DTG + 3TC in Suppressed Pts

97% (101/104) remained suppressed through 40 wks of dual therapy (study Wk 48)[1]

– No INSTI resistance in 3 pts with virologic failure

– 7 with SAEs, only 2 related to dual therapy

Switch to DTG-based dual therapy vs continued triple ART currently under evaluation in several phase III trials[2,3]

1. Joly V, et al. CROI 2017. Abstract 458. 2. ClinicalTrials.gov. NCT02263326. 3. ClinicalTrials.gov. NCT02486133.

Therapeutic Success, n/N* (%) DTG + 3TC

Wk 0 (entry; on BL triple therapy) 110/110 (100)

Wk 8 (end of phase I, start of phase II) 104/104 (100)

Wk 12 104/104 (100)

Wk 16 103/104 (99)

Wk 24 103/104 (99)

Wk 32 103/104 (99)

Wk 40 102/104 (98)

Wk 48 101/104 (97)

*Pts enrolled in phase I, N = 110; pts enrolled in phase II, N = 104.

DOMOMO: Switch to DTG Monotherapy in Virologically Suppressed Pts

Randomized comparison: switch to DTG monotherapy vs continued baseline ART for 24 wks in suppressed pts without previous VF[2]

At Wk 24, DTG monotherapy noninferior to continued baseline ART (VL <200)

– After 24 wks, all pts allowed to switch to monotherapy

Study stopped early because of high VF rate after 48 wks of monotherapy

– VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent control group (P = .03)

– Among 6 VF cases with resistance data in DTG monotherapy group, 3 developed INSTI resistance

Wijting I, et al. CROI 2017. Abstract 451LB.

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Emergent INSTI Resistance After Switch to DTG Monotherapy

International, multicenter retrospective study – Evaluated virologically

suppressed pts switched to DTG monotherapy

– Pts with history of VF on INSTI and INSTI resistance excluded

11 of 122 pts (9%) switched to DTG monotherapy experienced VF– 9 of 11 had genotypic INSTI

resistance at VF

INSTI resistance pathways varied

Blanco JL, et al. CROI 2017. Abstract 42.

INSTI Resistance at VF

92Q/155H (n = 1)

97A/155H (n = 1)

155H/148R (n = 1)

118R (n = 2)

148K (n = 1)

148H (n = 2)

148R (n = 1)

Investigational Drugs

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18

Doravirine vs. DRV/r at Wk 48FDA Snapshot

Efficacy similar in both arms regardless of baseline VL or CD4 count

No resistance detected in pts with PDVF through Wk 48 in either arm

– n = 1 pt with noncompliance discontinued at Wk 24, developed DOR and FTC resistance

Molina JM, et al. CROI 2017. Abstract 45LB.

Virologic Nonresponse

Wk 48

HIV-1 RNA< 50 c/mL

No Data

100

80

60

40

20

0

Pts

(%

)

84 80

11 135 7

Treatment difference: 3.9% (95% CI: -1.6% to 9.4%)

DOR + 2 NRTIs (n = 383)DRV/r + 2 NRTIs (n = 383)

Doravirine vs DRV/r in Combination With FTC/TDF or ABC/3TC: Safety

Molina JM, et al. CROI 2017. Abstract 45LB.

AE, %DOR

(n = 383)DRV/r

(n = 383)

≥ 1 AE 80 78

Treatment-related AE 31 32

Serious AE 5 6

Discontinuation for AE 2 3

AEs of clinical interest Rash* Neuropsychiatric†

711

813

Fasting Lipid Δ From BL to Wk 48, mg/dL

DOR(n = 383)

DRV/r(n = 383)

LDL-c* -4.51 9.92

Non-HDL-c* -5.3 13.75

Cholesterol -1.37 17.9

Triglyceride -3.14 21.97

HDL-c 3.94 4.15

*Discontinued due to rash: n = 2 in DOR arm; n = 1 in DRV/r arm.†No discontinuation for neuropsychiatric conditions.

*P < .0001 for DOR vs DRV + RTV.

5/10/2017

19

Bictegravir + FTC/TAF vs DTG + FTC/TAF in Treatment-Naive Pts

Bictegravir: novel QD INSTI, active against most INSTI mutations, low DDI potential, half-life ~ 18 hrs, no food requirement with dosing, primarily metabolized by CYP3A4 and UGT1A1

Randomized, double-blind, active-controlled phase II trial

– Primary endpoint: VL < 50 at Wk 24

Open-label extension

Sax PE, et al. CROI 2017. Abstract 41. Sax PE, et al. Lancet HIV. 2017;[Epubahead of print]. Zhang H, et al. CROI 2017. Abstract 40.

Wk 48

BIC + FTC/TAF QD +Placebo for DTG QD

(n = 65)

DTG + FTC/TAF QD +Placebo for BIC QD

(n = 33)

Wk 24

ART-naive ptswith VL ≥ 1000;

CD4 ≥ 200;HBV and HCV negative

(N = 98)

Bictegravir + FTC/TAF vs DTG + FTC/TAF: Wk 24 and Wk 48 Efficacy (FDA Snapshot)

No drug resistance detected in either arm through Wk 48

Sax PE, et al. CROI 2017. Abstract 41.

Virologic Failure

Wk 48

Virologic Success

No Data

100

80

60

40

20

0

9791

2 6 2 3

Treatment difference: 6.4% (95% CI: -6% to 18.8%)

Virologic FailureWk 24

Virologic Success

No Data

100

80

60

40

20

0

Pts

(%

)

97 94

3 6 0 0

Treatment difference: 2.9% (95% CI: -8.5% to 14.2%)

BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33)

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Difficult to drawn conclusions on safety from small study, but 4 fully enrolled phase III trials in progress now evaluating efficacy, safety, tolerability of coformulated BIC/FTC/TAF

Bictegravir + FTC/TAF vs DTG + FTC/TAF: AEs and Lab Abnormalities

Sax PE, et al. CROI 2017. Abstract 41. Reproduced with permission.

Any Grade AE Occurring in ≥ 5% in Either Arm, %

BIC + FTC/TAF(n = 65)

DTG + FTC/TAF(n = 33)

Diarrhea 12 12

Nausea 8 12

Headache 8 3

URTI 8 0

Fatigue 6 6

Arthralgia 6 6

Chlamydial infection 6 3

Back pain 6 0

Furuncle 5 6

Flatulence 2 6

Gastroenteritis 2 6

Costochondritis 0 6

Hemorrhoids 0 6

Pruritus 0 6

Grade 2-4 Lab Abnormality ≥ 5% in Either Arm, %

BIC + FTC/TAF(n = 64*)

DTG + FTC/TAF(n = 32*)

Creatine kinase 13 9

AST 9 3

Hyperglycemia 8 13

ALT 6 0

LDL 6 9

Amylase 5 6

Hematuria 3 6

Glycosuria 2 6

*Pts with ≥ 1 post-BL laboratory assessment, excluding those not specified for all pts.

Sax PE, et al. CROI 2017. Abstract 41.

LATTE-2: IM cabotegravir + rilpivirineWeek 48 Results: VL <50 Snapshot (ITT-ME)

Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

Snapshot success

D1 W32

Q4W 99% 94%

Q8W 95% 95%

Oral 98% 91%Pro

po

rtio

n o

f p

atie

nts

wit

h

viro

log

ical

su

pp

ress

ion

, %

BL W-16 W-12 W-8 D1 W4 W8 W12 W16 W20 W24 W28 W32

Study visit

Induction period Maintenance period

W-4 W36 W40 W44 W48

Oral CAB induction (ME population) Oral CAB (n=56) Q4W IM (n=115) Q8W IM (n=115)

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LATTE-2 VL <50 at Week 48 ITT-ME (Snapshot)

Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

Oral IM

Virologic outcomes Treatment differences (95% CI)

-6.6 12.4

Q8W IM

-7.6 11.6

Q4W IM

Both Q8W and Q4W comparable to Oral CAB at Week 48a

2 subjects with resistance in 8 wk arm: 1 with INSTI mutations, 1 with NNRTI mutations

Active phosphorylated metabolite has prolonged intracellular half-life in PMBCs: 150-160 hrs

Exploratory study of single 10 mg oral dose in HIV infected volunteers

Potential for novel dosing or administration strategies

MK-8591: Long-acting NRTI

Grobler J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 98;Friedman E, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 437LB.

-2.5

-2

-1.5

-1

-0.5

0

0.5

0 5 10 15 20

Ch

ang

e F

rom

Bas

elin

e V

L

(lo

g10

c/m

L)

Time (days)

TDF - 300 mg QD

TAF - 25 mg QD

MK-8591 - 10 mg QW

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Possible Long Acting SubdermalImplantable Devices for TAF Delivery

Gunawardana M et al. Antimicrob. Agents Chemother. 2015;59:3913-3919. Johnson L, et al. CROI 2016. #879.

• Silicone scaffold diffusion system1

• Long-acting biodegradable polycaprolactone thin-film membrane2

TMB-301: Long-Acting Ibalizumab in Pretreated Pts Infected With Multidrug-Resistant HIV

Humanized mAb to conformational epitope on CD4 receptor that blocks postattachment HIV entry into CD4 cells without altering normal cell function

Single-arm, open-label phase III trial

– Primary endpoint: ≥ 0.5 log10 VL decrease at Day 14

53% with resistance to all drugs from ≥ 3 classes; 68% with INSTI resistance

Lewis S, et al. CROI 2017. Abstract 449LB.

VL> 1000; on ART ≥ 6 mos, on stable ART ≥ 8 wks;

resistant to ≥ 1 ARV from 3 classes, sensitive to ≥ 1 ARV

for OBR (N = 40)

Wk 25

Ibalizumab2000 mg IV Day 7

(loading dose)Continue Failing ART

Days 0-14

Ibalizumab800 mg IV Day 21, Q2W

(maintenance dose)Switch to OBR

Day 14

Primary Endpoint:Day 14Control Period:

Day 0-7

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Efficacy, Safety of Ibalizumab Through 24 Wks

1o endpoint: 83% with ≥ 0.5 log10 VL decrease at Day 14 vs 3% at end of control period (P < .0001)

60% with ≥ 1.0 log10 VL decrease

Mean decrease by Day 14: 1.1 log10

9 pts reported 17 serious AEs

– 1 drug-related serious AE (IRIS) resulted in discontinuation

9 other pts discontinued

– Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma)

– Consent withdrawal (n = 3)

– Lost to follow-up (n = 2)

No cases of anti-ibalizumabantibodies

Lewis S, et al. CROI 2017. Abstract 449LB.

Wk 24 Virologic OutcomeIbalizumab +

OBR

≥ 1.0 log10 VL decrease, % 55

≥ 2.0 log10 VL decrease, % 48

VL < 50, % 43

VL < 200, % 50

Mean VL decrease from baseline, log10

1.6

AgentMoA or

FormulationPhase

Dosing/Administration

Implications

GS-CA1[1] HIV capsid inhibitorPre-

clinical

Extended release, suitable for SC of solid

depot formulation

Potent ART with orthoganol resistance profile to existing ART; potential for long-acting formulation due to low aqueous solubility, high stability

GS-9131[2] NRTIPre-

clinical

Potential for once daily dosing

Potent ART active against NRTI RAMs K65R, L74V, M184V alone or in combination; minimal loss of susceptibility with 4 or more TAMs

MK-8591[3]

Nucleoside Reverse Transcriptase Translocation

Inhibitor (NRTTI)

Pre-clinica

l

10 mg QW PO; potential for extended duration

Comparable MK-8591 levels in animal rectal, vaginal tissue to TDF levels in tissues of human subjects highlights potential prophylaxis utility

GS-PI1[4] PIPre-

clinical

Potential for unboosted, once daily dosing

Potent ART with high barrier to resistance, including < 2-fold loss in potency against major PI RAMs, and 10-fold to 40-fold longer in vivo half life vs ATV or DRV

NANO-EFV, NANO-LPV[5]

Oral, lower dose SDN

InEFV: 50 mg QD, 21 dnLPV/RTV: 200/100 mg

BID, 7 d

Enhanced oral bioavailability suggests can reduce EFV, LPV dose by ~ 50% while maintaining PK

Additional Investigational Agents Reported at CROI 2017: Preclinical and Phase I

1. Tse WC, et al. CROI 2017. Abstract 38. 2. White KL, et al. CROI 2017. Abstract 436. 3. Grobler J, et al. CROI 2017. Abstract 435. 4. Link JO, et al. CROI 2017. Abstract 433. 5. Owen A, et al. CROI 2017. Abstract 39.

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Additional Investigational Agents Reported at CROI 2017: Phase II

1. Bekker L-G, et al. CROI 2017. Abstract 421LB. 2. Murphy R, et al. CROI 2017. Abstract 452LB. 3. Wang C-Y, et al. CROI 2017. Abstract 450LB. 4. Lalezari J, et al. CROI 2017. Abstract 437.

AgentMoA or

FormulationPhase

Dosing/ Administration

Implications

TMC278 LA[1] LA injectable RPV (IM)

II 1200 mg IM Q8W Potential as injectable, long-acting PrEP

Elsulfavirine[2]Prodrug of new NNRTI VM1500A

IIb

Combined therapy: 20 mg

elsulfavirine + FTC/TDF PO QD

Less toxic alternative to EFV for initial ART

UB-421[3] Anti-CD4 receptor mAb

II10 mg/kg QW IV

or 25 mg/kg Q2W IV

Possible ART alternative for maintenance therapy in virologically suppressed pts

PRO-140[4]Anti-CCR5

mAbIIb 350 mg SC/wk

Being studied for both monotherapy and combination therapy

Conclusions

Integrase inhibitor-based regimens are now the standard of care for initial therapy

TAF/FTC is the preferred NRTI backbone for all regimens except DTG/ABC/3TC

Some regimens allow for immediate ART initiation while awaiting baseline labs results

Switching from TDF to TAF increases bone density and eGFR and decreases proteinuria

Stay tuned for The Great Debate: 3 drugs vs. 2

DTG resistance can happen but is rare…

…except with DTG monotherapy. Don’t do it!

New drugs keep coming, including long-acting agents

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Thank you!