Didactic Series - PAETCpaetc.org/wp-content/uploads/2016/12/New-ART-HIVLN-7.14... · 2016-12-20 ·...

1

Didactic Series

CROI 2016 - New Antiretroviral Therapies

Daniel Lee, MD

Clinical Professor of Medicine

UCSD Medical Center – Owen Clinic

July 14, 2016

This project is supported by the Health Resources and Services

Administration (HRSA) of the U.S. Department of Health and Human

Services (HHS) under grant number and title for grant amount (#

U1OHA29292-01-01, Regional AIDS Education and Training

Centers,

3

New Antiretroviral

Therapies

4

Question #1: Where do you feel is

the need for new antiretroviral

therapies for the future?

1) New single tablet regimens

2) ART with novel mechanisms of action

3) ART for experienced patients

4) Parenteral ART (non-tablet formulations)

5) ART with longer dosing intervals

6) Reductive ART (<3 meds per regimen)

RCT,DB,

dose-finding,

2-part study

Patients:

• HIV-1+ ART naïve

• RNA ≥1,000 c/mL

• CD4 ≥100 cells/µL

• Stratified by screening

RNA (≤/>100k c/mL)

Part 2 began after

dose selection based

on Part 1 week

24 results.

Part 1 Dose Ranging Phase

(N=210)

Part 1

Extension Phase

DOR 25 mg

DOR 50 mg

DOR 100 mg (n=42) DOR 100 mg

DOR 200 mg

EFV 600 mg (n=43) Continue EFV

Part 2: Additional Patients, DOR Selected Dose vs EFV

(N=132)

DOR 100 mg (n=66)

EFV 600 mg (n=66)

Study 007: DOR 100 mg QD vs. EFV +TDF/FTC in Naive HIV+ Patients – Week 48 Results

Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 470.

Study Design

Week 48

Week 48

Week 96

Week 96

Study 007: Results HIV RNA <40 copies/mL


3,7

15,7

27,8

42,1

63,0

73,1 77,8

78,7

6,5 12,0

26,9

47,2

57,5

72,9

81,5

77,8

0

10

20

30

40

50

60

70

80

90

100

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

% o

f p

ati

en

ts (

95

% C

I)

Treatment Week

DOR 100 mg + TDF/FTC

EFV 600 mg + TDF/FTC

Week 48 n/N (%)

DOR 84/108 (77.8)

EFV 85/108 (78.7)

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

(NC=F Approach)

Study 007: Results Virologic Response by Screening RNA


88,6 89,6 74,3

91,4 87,1 91,9 83,8

91,9

0

20

40

60

80

100

% <40 c/mL % <200 c/mL % <40 c/mL % <200 c/mL

DOR 100 mg + TDF/FTC EFV 600 mg + TDF/FTC

≤100,000 c/mL >100,000 c/mL

n/N: 58/67 54/62 60/67 57/62 26/35 31/37 32/35 34/37

Week 48 (OF Approach)

Pe

rce

nt

of

Su

bje

cts

(9

5%

CI)

Study 007: Adverse Events

DOR 100 mg

(N=108)

EFV 600 mg

(N=108)

Difference

[DOR – EFV]

(95% CI)

One or more adverse events (AE) 87.0 88.9 -1.9 (-10.9, 7.1)

Serious AE 6.5 8.3 -1.9 (-9.5, 5.6)

Death 0 0

Discontinued due to AE 2.8 5.6 -2.8 (-9.2, 3.0)

Drug-related AE 31.5 56.5 -25.0 (-37.3, -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 -- Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 470.

LATTE-2 Study: Maintenance Therapy with Injectable Cabotegravir and Rilpivirine

Induction period

Week 32

Primary analysis

Dosing regimen

selection

Day 1

Randomization

2:2:1

Week 48

Analysis

Dosing regimen

confirmation

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

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

CAB 30 mg + ABC/3TC PO QD (n=56)

Week 96

CAB loading dose at Day 1

CAB loading doses at Day 1 and Week 4

CAB 30 mg +

ABC/3TC for

20 weeks

(N=309)

Maintenance period

Add RPV

4 weeks

Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 31LB.

LATTE-2 Study: Week 32 Primary Endpoint: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)

• No resistance detected in any study arm

• 82% experienced grade 1 injection site reactions, 17% grade 2 (moderate) – most commonly pain, swelling, or nodules; one death (epilepsy), cause unclear

• Suppressive ART with IM cabotegravir and rilpivirine appears safe and effective; further studies planned

Virologic Outcomes Treatment Differences (95% CI)

Oral

-4.8 12.2

Q8W

-5.8 11.5

Q4W

IM


4 5

91

4 5

0

20

40

60

80

100

Virologicsuccess

Virologicnon-response

No virologicdata

HIV

-1 R

NA

<5

0 c

/mL

, %

Q8W (n=115)

Q4W (n=115)

oral CAB (n=56)

95* 94*

<1 <1

How satisfied are you with

your current treatment? How satisfied would you be to continue

with your present form of treatment?

97% 96% 71%

29%

0%

20%

40%

60%

80%

100%

Q8W (n=106) Q4W (n=100) Oral CAB (n=49)

More Neutral Less

98% 98% 71%

29%

0%

20%

40%

60%

80%

100%

Q8W (n=106) Q4W (n=100) Oral CAB (n=49)

More Neutral Less

3% 3% 2%

1%

1%

1%


LATTE-2 Study: Patient Outcomes Comparing Maintenance with Oral Induction Treatment

Pa

tie

nt P

erc

en

t

Long-term follow-up through Week 96 (BMS-663068 1200 mg QD) Week 96

BMS-663068 1200mg QD was selected as the open-label continuation dose after Week 48

AI438011 Study: BMS-663068 Oral HIV Attachment Inhibitor – 96 Week Results

DeJesus E, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 472.

Primary study – start of combination therapy Day 1

Data monitoring committee assessment Day 8

Primary endpoint Week 24

Long-term follow-up through Week 48 (secondary endpoint) Week 48

BMS-663068 monotherapy sub-study: 10 subjects per study arm

BMS-663068

400 mg BID

+ RAL +TDF

N=50

BMS-663068

800 mg BID

+ RAL +TDF

N=50

BMS-663068

600 mg QD

+ RAL +TDF

N=50

BMS-663068

1200 mg QD

+ RAL +TDF

N=50

ATV/r

300/100 mg OD

+ RAL +TDF

N=50

Study Design

AI438011 Study: Results

DeJesus E, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 472.

Pro

po

rtio

n o

f s

ub

jec

ts a

ch

ievin

g H

IV-1

RN

A <

50

c/m

L, %

(95

% C

l)

0 2 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96

100

90

80

70

60

50

40

30

20

10

0

Week

Proportion of subjects with

<50 c/mL through Week 96

BMS-663068

1,200 mg QD 90%

ATV/r 300 mg/

100 mg QD 90%

• NRTI with unique mechanism of action and unusual PK

• Active phosphorylated metabolite has prolonged intracellular persistence in human PMBCs, with half-life of 150-160 hours

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

• MK-8591, a novel NRT translocation inhibitor, suppresses HIV RNA by 1.75 log after a single dose – long half life could lead to 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

an

ge

Fro

m B

as

eli

ne

HIV

-1 R

NA

(l

og

10 c

/mL

)

Time (days)

TDF - 300 mg QD

TAF - 25 mg QD

MK-8591 - 10 mg QW

Date of download: 7/13/2016 Copyright © 2016 American Medical

Association. All rights reserved.

From: Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of

the International Antiviral Society–USA Panel

JAMA. 2016;316(2):191-210. doi:10.1001/jama.2016.8900

Recommended Initial Antiretroviral Therapy Regimensa

Table Title:





JAMA. 2016;316(2):191-210. doi:10.1001/jama.2016.8900

Advantages and Disadvantages of Currently Available Integrase Strand Transfer Inhibitors

Table Title:





JAMA. 2016;316(2):191-210. doi:10.1001/jama.2016.8900

Advantages and Disadvantages of Initial Antiretroviral Therapy Options for Patients in Whom InSTIs Are Not an Optiona

Table Title:

18

References

• Slides are courtesy from

– ViralEd CME Internet Symposium: CROI 2016 Expert

Review

• http://www.viraled.com/modules/info/croi_2016_cme_internet

_symposium_croi_2016_expert.html

– Clinical Care Options

• http://www.clinicaloptions.com/

• 2016 Conference on Retroviruses and

Opportunistic Infections

– http://www.croiconference.org/

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