Antiretroviral Therapy in 2016 - .: REGENCY · Antiretroviral Therapy in 2016 . Disclosures...

Joel Gallant, MD, MPH

Southwest CARE Center

Santa Fe, NM

University of New Mexico School of Medicine

Johns Hopkins University School of Medicine

Antiretroviral Therapy in 2016

Disclosures

Consulting, Advisory Boards, and DSMBs

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Merck & Co.

ViiV Healthcare

Research Support

AbbVie

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Merck & Co.

Sangamo BioSciences

ViiV Healthcare

When to Start

START: Immediate vs Deferred Therapy

for Asymptomatic, ART-Naive Pts

International, randomized trial

Composite 1o endpoint: Serious AIDS-related (AIDS-related death or AIDS-defining event) or non-AIDS–related event (non-AIDS–related death, CVD, end-stage renal disease, decompensated liver disease, non-AIDS–defining cancer)

Median follow-up: 3.0 yrs; med. baseline CD4: 651; med. baseline VL: 12,759

Med. CD4 at initiation of ART for deferred group: 408

Immediate ART

ART initiated immediately

following randomization

(n = 2326)

Lundgren J, et al. N Engl J Med. 2015

Deferred ART

Deferred until CD4 ≤ 350,

AIDS, or event requiring ART

(n = 2359)

HIV+, ART-naive

adults with CD4 > 500

(N = 4685)

Study closed by DSMB

following interim analysis

START: 57% Reduced Risk of Serious Events or

Death With Immediate ART

1.8% vs 4.1% in deferred vs immediate arms experienced serious AIDS or non-AIDS related event or death: HR = 0.43 (95% CI: 0.30 to 0.62); P < .001

10

8

6

4

2

0

Cum

ula

tive

Pe

rcen

t W

ith E

ve

nt

0 6 12 18 24 30 36 42 48 54 60

Month

Deferred ART

Immediate ART


START: Primary Endpoint Components With

Immediate vs Deferred ART

Endpoint Immediate ART

(n = 2326)

Deferred ART

(n = 2359)

HR

(95% CI)*

P Value

N Rate/100 PY N Rate/100 PY

Serious AIDS-related event 14 0.20 50 0.72 0.28

(0.15-0.50) < .001

Serious non-AIDS–related event 29 0.42 47 0.67 0.61

(0.38-0.97) .04

All-cause death 12 0.17 21 0.30 0.58

(0.28-1.17) .13

Tuberculosis 6 0.09 20 0.28 0.29

(0.12-0.73) .008

Kaposi’s sarcoma 1 0.01 11 0.16 0.09

(0.01-0.71) .02

Malignant lymphoma 3 0.04 10 0.14 0.30

(0.08-1.10) .07

Non-AIDS–defining cancer 9 0.13 18 0.26 0.50

(0.22-1.11) .09

CVD 12 0.17 14 0.20 0.84

(0.39-1.81) .65


START: Cancer Events With Immediate vs

Deferred ART

Cancer Event, n

Immediate

ART

(n = 2326)

Deferred

ART

(n =

2359)

Total 14 39

Kaposi’s sarcoma 1 11

Lymphoma, NHL +

HL 3 10

Prostate cancer 2 3

Lung cancer 2 2

Anal cancer 1 2

Cervical or testis

cancer 1 2

Other types* 4 9

Time to Cancer Event

10

8

6

4

2

0 Cu

mu

lative

% W

ith

Eve

nt

0 12 24 36 48 60

Months

*Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma.

Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid

cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck.


Deferred ART

Immediate ART

Rate/100 PY: immediate, 0.20; delayed, 0.56

HR (immediate vs delayed):

0.36 (95%CI: 0.19 to 0.66, P = .001)

START:

Primary Endpoint Events By Latest CD4 Count

Latest CD4 > 500

Immediat

e ART

Deferred

ART

% of

Primary

Events

88%

(37/42)

59%

(57/96)

Rate/100

PY

0.6 1.1

Immediate ART Deferred ART

Pe

rce

nt o

f F

ollo

w-u

p T

ime

Latest CD4 Count

60

50

40

30

20

10

0

2

(4.7)

No. of Pts with Events

(Rates/100 PY)

No. of Pts with Events

(Rates/100 PY)

3

(0.8)

6

(0.4)

11

(0.6)

20

(0.6)

5

(1.8)

34

(2.0)

34

(1.5)

9

(0.6)

14

(1.1)


When to Start: DHHS Guidelines, January 2016

US DHHS Guidelines, January 2016

ART recommended for all HIV+ individuals to reduce risk of disease

progression. Strength and evidence for recommendation vary by pre-

treatment CD4 count (AI)

ART recommended for HIV-infected individuals for prevention of HIV

transmission (AI)

When to Start?: Guidelines

AIDS/

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

What to Start

DHHS Guidelines, January 2016

What to Start

Recommended regimens

Boosted PI-based DRV/r + FTC/TDF

INSTI-based RAL + FTCTDF

EVG/COBI/FTC/TDF

DTG + FTC/TDF

DTG/3TC/ABC

EVG/COBI/FTC/TAF

Alternative regimens

NNRTI-based EFV/FTC/TDF

RPV/FTC/TDF (VL <100,000; CD4 >200)

PI-based ATV/c + FTC/TDF (CrCl >70)

ATV/r + FTC/TDF

(DRV/c or DRV/r) + 3TC/ABC

DRV/c + FTC/TDF (CrCl >70)

DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, January 2016

The 5 most common initial regimens we’ll

now be using in the U.S.

INSTI-based EVG/COBI/FTC/TAF (Genvoya)

DTG + FTC/TAF (Tivicay + Descovy)

DTG/3TC/ABC (Triumeq)

PI-based DRV/c + FTC/TAF (Prezcobix + Descovy)

NNRTI-based RPV/FTC/TAF (Odefsey)

Drugs I left out

Disadvantages Advantages

INSTI

RAL

Twice daily (for now)

Lower resistance barrier than

DTG

Tolerability

Few drug interactions

PI

ATV

Jaundice

Nephrotoxicity

Cholelithiasis

Nephrolithiasis

More GI effects than DRV

Gastric acid requirement

The only PI that can be

given without boosting

An option for patients with

DRV rash

LPV/r

Higher pill burden

More GI effects

More metabolic effects

Low cost

NNRTI

EFV

CNS side effects

Rash

Resistance

Low cost

NRTI AZT

Twice daily dosing

Toxicity Low cost

SINGLE: Dolutegravir + ABC/3TC vs.

EFV/TDF/FTC

Week

EFV/TDF/FTC QD

DTG 50 mg + ABC/3TC QD

BL 2 4 8 12 16 24 32 40 48

0

10

20

30

40

50

60

70

80

90

100

Pro

po

rtio

n (

%)

wit

h <

50

c/m

L

DTG+ABC/3TC: 88%

EFV/TDF/FTC: 81%

WK 48 difference in response (95% CI):

+7.4% (+2.5% to +12.3%); p=0.003

● DTG + ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1o endpoint)

Walmsley S, et al. N Engl J Med 2013;369:1807-18

STRIIVING:

Switch to DTG/ABC/3TC

Ongoing randomized, open-label phase IIIB study

– Primary endpoint: VL < 50 at Wk 24

VL < 50 on stable ART ≥ 6

mos; no previous virologic

failure; HLA-B*5701

negative

(N = 551)

DTG/ABC/3TC (n = 274)

Wk 48 Wk 24

Trottier B, et al. ICAAC 2015.

*Containing 2 NRTIs plus NNRTI, PI, or INSTI.

Baseline ART* (n = 277)

DTG/ABC/3TC (n = 277)

PI NNRTI INSTI TDF/FTC

BL ART use, % 42 31 26 77

STRIIVING: Study Disposition at Wk 24


13% of subjects withdrawn (n = 35)

Adverse event 10 (4%)

Lack of efficacy (virologic failure) 0

Protocol deviation 15 (5%)

Stopping criteria met 0

Lost to follow-up 3 (1%)

Investigator discretion 3 (1%)

Withdrew consent 4 (1%)

87% completed (n = 239)

Screened

(N = 841)

12% of subjects withdrawn (n = 32)

Adverse event 0

Lack of efficacy (virologic failure) 0

Protocol deviation 17 (6%)

Stopping criteria met 0

Lost to follow-up 3 (1%)

Investigator discretion 3 (1%)

Withdrew consent 9 (3%)

Randomized and treated Baseline ART (n = 277)

88% completed (n = 244) 1 with missing information

Randomized and treated DTG/ABC/3TC (n = 274)

5 2

STRIIVING: Virologic Outcomes at Wk 24

Switch noninferior to maintaining baseline ART

No protocol-defined virologic failure

– 3 pts in DTG/ABC/3TC arm (1%) and 4 pts in BL ART arm (1%) had VL 50-100 through Wk 24


Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations

100

80

60

40

20

0 Virologic

Success

Virologic

Nonresponse

No Virologic

Data

VL <

50 (

%)

DTG/ABC/3TC (ITT-E, n = 274)

Baseline ART (ITT-E, n = 277)

DTG/ABC/3TC (PP, n = 220)

Baseline ART (PP, n = 215)

85 88 93 93

14 10 6 1 1 < 1

12 -12 -8 -4 0 4 8

12 -12 -8 -4 0 4 8

-4.9

-0.3

4.4

2.3 -9.1

ITT-E Population

PP Population

-3.4

DTG/ABC/3TC Baseline ART

STRIIVING: Adverse Events and Treatment

Satisfaction

10 pts discontinued for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm

Greater increase in treatment satisfaction score from baseline to Wk 24 in DTG/ABC/3TC arm

vs baseline ART arm: adjusted mean difference: 2.4 (P < .001)


AEs in 10 Pts Who Withdrew* Grade

Insomnia 2

Diarrhea, flatulence, rash

Abdominal pain, anxiety, nausea, body ache

1

2

Euphoric mood

Headache

1

2

Abdominal cramps, chills, diarrhea,

dizziness,

headache

2

Pruritus 2

Abdominal pain, diarrhea, flulike syndrome,

profuse sweating, change in body odor

Fatigue,† malaise, depression

1

2

Nasal congestion

Worsening fatigue

Nausea

1

2

3

Alopecia 1

Fatigue† 1

Homicide† N/A

*None serious AEs except homicide. †Not drug related.

LYMPHOCYTE

TFV

TFV

RENAL

TUBULAR

CELL

RENAL

TUBULAR

CELL

91% lower

plasma TFV

HIV

PLASMA GI

TRACT

TDF (tenofovir

disoproxil

fumarate)

300 mg

TAF (tenofovir

alafenamid

e)

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.

Virologic

Success*

Virologic

Failure

No Data

GS 104/111: E/C/F/TAF noninferior to E/C/F/TDF at week 48

Results similar across all baseline virologic and demographic subgroups

7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at VF

– 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R

– 5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF P

atients

, %

92 90

Δ +2.0%

(95% CI: -0.7% to +4.7)

TAF/FTC/EVG/COBI

(n = 866)

TDF/FTC/EVG/COBI

(n = 867)

0

20

40

60

80

100

4 4 4 6

n =

*VL < 50 as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data.

800 784

Sax P, et al. Lancet 2015;385:2606-15.

Randomized, active-controlled, open-label study

Primary endpoint: proportion of patients with VL < 50 after 48 wks

GS-109: Switching From TDF- to TAF-based

Regimens in Virologically Suppressed Pts

Mills A, et al. Lancet Infect Dis 2016;16:43-52

Pts with VL < 50

(≥ 96 wks) and eGFR >

50 mL/min on stable

TDF-based regimen for

≥ 48 wks

(N = 1436)

EVG/COBI/FTC/TAF QD

(n = 959)

Continue previous TDF-based regimen†

(n = 477)

Primary Endpoint Wk 48

Continue

through

Wk 96

GS-109: Switching to E/C/F/TAF from TDF-

based regimens


100

80

60

40

20

0

Wk 4

8 V

L <

50

, %

All Prior

Regimens

Prior

EFV/TDF/FTC

Prior

Boosted

ATV + TDF/FTC

Prior

EVG/COBI/

FTC/TDF

EVG/COBI/FTC/TAF TDF-Based Regimen Primary Endpoint

P < .001 P = .02 P = .02 P = NS

97 93

96 90

97 92

98 97

932/

959

444/

477

241/

251

112/

125

390/

402

183/

199

301/

306 149/

153 n/N =

GS 1089: Switch from F/TDF to F/TAF

Randomized, double-blind, double-dummy, active-controlled study

*F/TAF Dose:

• 200/10 mg with boosted PIs

• 200/25 mg with unboosted third agents

Secondary

Endpoint

n=333

n=330

Primary Endpoint

HIV-1 RNA <50 c/mL

BL Wk 96 Wk 48

F/TAF (200/10 or 200/25 mg)* QD

F/TDF Placebo QD

Continue Third Agent

F/TDF (200/300 mg) QD

F/TAF* Placebo QD

Continue Third Agent

VL <50 on F/TDF + Third

Agent

eGFR ≥50 mL/min

Gallant J, et al. Lancet HIV 2016;3:e158-65

GS 1089: Efficacy at Week 48 (Snapshot)

F/TDF F/TAF

0

VL <

50,

%

‒10% +10%

5.1 -2.5

1.3

Non-success

Treatment Difference (95% CI) Virologic Outcome


TAF: Renal safety

GS104/111: E/C/F/TAF vs. E/C/F/TDF: Renal Safety

n (%) E/C/F/TAF

n=866

E/C/F/TDF

n=867

Events

Renal adverse events leading to

discontinuation 0 4 (0.5)

Tubulopathy/Fanconi syndrome 0 0

Me

an

(S

D)

Ch

an

ge

fr

om

Ba

se

lin

e e

GF

R*

Time (Weeks)

E/C/F/TAF

E/C/F/TDF

0 0 12 24 36 48

20

10

0

-10

-20

-6.6 p <0.001

-11.2

Sax P, et al. Lancet 2015;385:2606-15.

GS 104/111: TAF vs. TDF: Quantitative

Proteinuria

Me

dia

n %

Ch

an

ge

fro

m B

as

eli

ne

(Q

1, Q

3) Protein

(UPCR) Albumin (UACR)

RBP Beta2-

microglobulin

p <0.001 for all

Urine [protein]:Creatinine Ratio

-3 -5

9

-32

20

7

51

24

-50

-25

0

25

50

75

76 133 168 E/C/F/TAF

E/C/F/TDF

Baseline 44

mg/g

44

mg/g

5

mg/g

5

mg/g

64

μg/g

67

μg/g

101

μg/g

103

μg/g

Sax P, et al. Lancet 2015;385:2606-15

Protein (UPCR)

Albumin (UACR)

RBP

GS 1089: Switch from F/TDF to F/TAF

Changes in eGFR

*eGFR calculated with Cockcroft-Gault equation

0 1 2 2 4 3 6 4 8

0

1 0

2 0F /T A F (n = 3 3 3 )

F /T D F (n = 3 3 0 )

W e e k s

Me

dia

n (

Q1

, Q

3)

ch

an

ge

eG

FR

* (

mL

/min

)

-10

8.4 mL/min

2.8 mL/min

p <0.001


RBP, retinol-binding protein; β2M, β2-microglobulin.

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

All differences between treatments statistically significant (p <0.001)

F/TAF

F/TDF

Albumin Protein β2M RBP

Urine Protein to Creatinine Ratio

Me

dia

n %

ch

an

ge


GS-112: Switching to E/C/F/TAF in patients

with kidney disease (eGFR 30-60)

Changes in eGFR to Wk 48

Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-7

Total TDF Non-TDF

Med

ian

Cha

ng

e

fro

m B

ase

line

10

0

-10

-0.6

+0.2

-1.8 -1.8* -1.5 -2.7*

Baseline: 56 58 53 54 56 50

eGFRCG

mL/min

eGFRCKD-EPI Cr

mL/min/1.73m2

*P < 0.05.

Multicenter, open-label phase III trial, N=242 (158 on TDF, 84 on non-TDF-based regimen)

TAF: Bone safety

3

2

GS104/111: E/C/F/TAF vs. E/C/F/TDF

Bone mineral density changes

0 24 48 0 24 48 0

-6

-4

-2

0

2

Wk Wk

0

-6

-4

-2

0

2

=845

=850

797

816

784

773

836

848

789

815

780

767

-1.30 -2.86

-0.66

-2.95

P < .001 P < .001

Me

an

% C

ha

nge

Fro

m B

L

Sax P, et al. Lancet 2015;385:2606-15

n

n

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

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

GS-109: Switch from TDF to TAF

Changes in bone density (spine)

Hip BMD similarly increased for pts treated with Genvoya


4

3

2

1

0

-1

-2

-3 Me

dia

n %

Ch

an

ge

(sp

ine

)

in B

MD

(Q

1, Q

3)

Baseline Week 24

EVG/COBI/FTC/TAF

TDF-Based Regimen

Week 48

1.79

-0.28

P < .001

B L 2 4 4 8

0

2

4

B L 2 4 4 8

0

2

4

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

35

≥ 3% BMD increase at Week 48

F/TAF 30.3% p<0.001

16.7% p=0.003

F/TDF 13.7% 8.6%

321 310 300

320 310 306

321 309 300

317 305 303

F/TAF, n

F/TDF, n

Me

an

% c

ha

ng

e (

95

% C

I) Spine

1.5

-0.2

1.1

-0.2

Weeks Weeks

p <0.001

Hip

p <0.001


What to Start: My Choices (no baseline resistance)

Regimen PROS CONS

EVG/COBI/FTC/TAF Single tablet

Advantages of TAF

Drug interactions

Potential for INSTI resistance

DTG/3TC/ABC Single tablet

High resistance barrier

Few drug interactions

HLA B*5701 testing

MI risk?

ABC: more AEs than TDF

DTG + FTC/TAF Advantages of DTG

Advantages of TAF

2-pill regimen

DRV/c + FTC/TAF No PI resistance with

failure

Advantages of TAF

2-pill regimen

More side effects than with

INSTIs

RPV/FTC/TAF Single tablet

Excellent tolerability

Advantages of TAF

Meal requirement

VL, CD4 requirement

Avoid acid-reducing agents

Choosing ART in special populations

Adherence concerns: – DRV/c + FTC/TAF – DTG/ABC/3TC (?)

Baseline genotype pending: – Avoid NNRTI-based regimens

HCV coinfection: – INSTI + either FTC/TAF or 3TC/ABC

HBV coinfection: – FTC/TAF-based regimens

Pregnancy: – Consult perinatal guidelines

New Drugs and Treatment Strategies

LATTE-2: IM Cabotegravir + Rilpivirine for

Long-Acting Maintenance Therapy

Multicenter, open-label phase IIb study

Primary endpoints: VL <50 by FDA snapshot, PDVF, and safety at maintenance Wk 32

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115)

*Pts with VL < 50 from Wk 16 to Wk 20 continued to maintenance phase. 6 pts discontinued for AEs or

death in induction analysis.

ART-naïve

pts with

CD4 > 200

(N = 309) CAB 30 mg PO + ABC/3TC PO QD

(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32

primary analysis;

dose selection

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96 Wk 16: RPV

PO added

LATTE-2: Maintenance Wk 32 Virologic

Efficacy (ITT-Maintenance Exposed)

Virologic efficacy of Q4W and Q8W IM regimens similar to oral regimen

No INSTI, NNRTI, or NRTI resistance mutations detected


95 94 91

4 < 1 4 < 1 5 5

Virologic

Success

Virologic

Non-

response

No

Virologic

Data

VL <

50 (

%)

100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)

IM CAB + RPV Q8W (n = 115)

Oral CAB + ABC/3TC (n = 56)

Treatment Differences (95% CI)

Q8W

-4.8

3.7

12.2

IM Oral

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

Q4W

-5.8

2.8

11.5

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

LATTE-2: Safety Through Maintenance

Wk 32

Most frequent ISRs were pain (67%), swelling (7%), and nodules (6%)

– ISR events/injection: 0.53

– 99% of ISRs grade 1/2; none grade 4

– Proportion of pts reporting ISRs decreased with time from 86% on Day 1 to 33% at Wk 32; 1% of pts withdrew for ISRs


AEs, % Pooled CAB + RPV IM Arms

(n = 230)

Oral CAB + ABC/3TC

(n = 56)

Drug-related grade 3/4 AEs

(excluding ISRs) 3 0

Serious AEs 6 5

AEs leading to withdrawal 3 2

LATTE-2: Wk 32 Pt Satisfaction With

Maintenance Therapy vs Oral Induction


Pts

(%

)

How satisfied are you with your

current treatment?

100

80

60

40

20

0 Q8W

(n = 106)

Q4W

(n = 100)

Oral CAB

(n = 49)

More Neutral Less

100

80

60

40

20

0 Q8W

(n = 106)

Q4W

(n = 100)

Oral CAB

(n = 49)

More Neutral Less

How satisfied would you be to continue with

your present form of treatment?

97 96 71

29

3 1

3

98 98 71

29

2 1

1

MK-1439-007: Doravirine + TDF/FTC vs

EFV + TDF/FTC In Treatment-Naive Pts

Doravirine: investigational NNRTI with activity against common NNRTI resistance mutations, QD dosing, no PPI drug–drug interactions, improved CNS safety vs EFV in early studies

Part 2 of 2-part randomized, double-blind phase II study

– Primary endpoint: VL < 40 c/mL at Wk 48

ART-naive HIV+ pts

with VL ≥ 1000,

CD4 ≥ 100

(N = 132)*

Wk 48

DOR 100 mg QD + TDF/FTC

(n = 66)

EFV 600 mg QD + TDF/FTC

(n = 66)

Wk 96

*42 pts receiving DOR 100 mg QD + TDF/FTC and 43 pts receiving EFV 600 mg QD + TDF/FTC

in part 1 of this study were included in this analysis.

Gatell JM, et al. CROI 2016. Abstract 470.

MK-1439-007: Primary Endpoint


78.7

77.8 77.8

81.5 73.1

72.9

57.5

63.0

42.1

26.9

47.2

27.8

12.0

15.7

6.5 3.7

0 4 8 12 16 20 24 28 32 36 40 44 48

100

80

60

40

20

0

Doravirine 100 mg

Efavirenz 600 mg

Wk 48 VL < 40 c/mL n/N (%)

Doravirine 84/108 (77.8)

Efavirenz 85/108 (78.7)

Difference (95% CI): -1.1 (-12.2 to 10.0)

Treatment Wk

VL <

40

(N

C =

F),

%

(95%

CI)

MK-1439-007: Clinical Adverse Events


Clinical AEs, % DOR + TDF/FTC

(n = 108)

EFV + TDF/FTC

(n = 108)

Difference,

DOR–EFV (95% CI)

≥ 1 AE 87.0 88.9 -1.9 (-10.9 to 7.1)

Serious AEs 6.5 8.3 -1.9 (-9.5 to 5.6)

Death 0 0

D/c for AEs 2.8 5.6 -2.8 (-9.2 to 3.0)

Drug-related AEs* 31.5 56.5 -25.0 (-37.3 to 11.8)

Diarrhea 0.9 6.5

Nausea 7.4 5.6

Dizziness 6.5 25.9

Headache 2.8 5.6

Abnormal dreams 5.6 14.8

Insomnia 6.5 2.8

Nightmares 5.6 8.3

Sleep disorder 4.6 6.5

*Specific AEs occurring in ≥ 5% of pts included.

PADDLE: All Pts Virologically Suppressed

by Wk 8 of DTG + 3TC

Included 4 pts with VL > 100,000 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 24

1 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

Switch From Suppressive ART to

DTG Monotherapy

97% maintained virologic suppression at Wk 24[1]

Reasons for switch improved in most pts from BL to 24 wks[1]

– T-scores unchanged in 2 pts with osteoporosis

– In single pt with renal disease, eGFR ↓ from 59 mL/min at BL to 52 mL/min/ at Wk 24; urine protein:creatinine ratio ↓ from 330 to 146 mg/mg

In separate study of switch from suppressive ART to DTG monotherapy, 89% of pts maintained virologic suppression 24 wks after switch[2]

1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714.

Reason for Switch Pts at Risk, n Outcome Improved/ Avoided, n

DDIs 13 13

GI symptoms 11 9

Dyslipidemia 9 9

High Framingham score 3 3

Evolution of Integrase Mutations in 2

DTG Monotherapy Switch Studies

All 4 pts with virologic failure had history of INSTI use before switch

1 pt had previous RAL failure but no INSTI resistance

1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714.

VL at VF,

c/mL

INSTI Resistance by Timepoint (Detection Source)

Day 0 Wk 4 Wk 12/13 Wk 24

155[1] - None (DNA) - 118R (DNA)

469[2]

L74I (DNA) - L74I, E92Q (RNA)

R: EVG RAL -

291[2] None (DNA) - -

155H (RNA)

R: EVG RAL

2220[2]

None (DNA) None (RNA) None (DNA)

E138K / G140A,

Q148R (RNA)

R: DTG EVG RAL

More in the pipeline

Ibalizumab: entry inhibitor

– monoclonal antibody binds CD4

– being studied for treatment and prevention

BMS 6630681: entry inhibitor

– Blocks attachment by binding to gp120

BMS 9551762: maturation inhibitor

– Disrupts processing of gag protein

– Trial in naïve pts planned

GS9883: integrase inhibitor

– Unboosted

– Potential for coformulation with TAF/FTC

1. Lalezari J et al. CROI 2014, Abstract 86.

2. Hwang C et al. CROI 2015, Abstract 114LB

Reasons to consider switching

therapy in suppressed patients

Older PIs:

– Reduce pill burden

– Decrease metabolic effects

– Decrease GI side effects

Older NRTIs:

– d4T, ddI: SWITCH! (toxicity)

– AZT: consider switch (toxicity, side effects, simplification)

TDF:

– If price the same, no advantage of TDF over TAF

Nevirapine:

– Reduce pill burden

– Not toxicity (most toxicity occurs with initiation)

Efavirenz:

– CNS side effects

– No TAF-based coformulation

Recent switch studies in suppressed pts Trial From To Outcome

GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF ✔

GS-264 TDF/FTC/EFV RPV/FTC/TDF ✔

Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF ✔

Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF ✔

SPIRIT 2 NRTI + PI/r RPV/FTC/TDF ✔

SPIRAL 2 NRTI + PI/r (exp’d pts) 2 NRTI + RAL ✔

SALT ATV/r + 2 NRTI ATV/r + 3TC ✔

OLE LPV/r + 2 NRTIs LPV/r + 3TC ✔

GS-109 TDF-based ART EVG/COBI/FTC/TAF ✔

STRIIVING Suppressive ART DTG/ABC/3TC ✔

ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC ✔

GS-119 “Salvage regimen” EVG/COBI/FTC/TAF + DRV ✔

LATTE CAB or EFV + 2 NRTIs CAB + RPV ✔

GS-1089 TDF/FTC + 3rd agent TAF/FTC + 3rd agent ✔

SWITHCMRK 2 NRTI + LPV/r (exp’d pts) 2 NRTI + RAL ✗

HARNESS 2 NRTI + 3rd Agent ATV/r + RAL ✗

Adapted from David Wohl

Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure

SWITCHMRK: Prior failure predicts failure

Eron JJ, et al. Lancet. 2010;375:396-407.

Outcome

SWITCHMRK1 SWITCHMRK 2

RAL

(n = 174)

LPV/r (n =

174)

RAL

(n = 176)

LPV/r (n =

178)

Patients without previous virologic failure

VL < 50 at Wk 24, % 85.1 85.8 92.5 93.5

Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3)

Patients with previous virologic failure

VL < 50 at Wk 24, % 72.3 89.7 79.7 93.8

Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)

Switching: Caveats

Know the treatment and resistance history

Avoid switching from high barrier to lower barrier agents when you don’t

Switching and simplifying therapy

“Vertical Switches”: switch to drug with lower resistance barrier

Most drug discontinuations

Boosted PI → NNRTI

Boosted PI → INSTI

Boosted PI → any STR

DRV/r twice daily → once daily

“Horizontal Switches”: switch to drug with equal or higher resistance barrier

RTV → COBI (boosters)

Switches within INSTI class

EFV or NVP → RPV or ETR

LPV/r or ATV/r → DRV/r

ABC or AZT → TDF/TAF

TDF → TAF

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