the future of antiretroviral therapy: new agents and...

The Future of Antiretroviral Therapy:

New Agents and Strategies

Brian R. Wood, MD

Associate Professor of Medicine

Medical Director, MW AETC HIV ECHO Telehealth Program

November 14, 2017

Get ready for audience polling!Go to: pollev.com/uwacc or download the Poll Everywhere app (username: uwacc)

Disclosures

I have no financial conflicts of interest.

I will be discussing investigational agents.

www.hiv.uw.edu

Outline: The Future of ART

Where are we now and what do we need most?

What’s coming?

New meds, combos, and formulations from existing classes

Agents with novel mechanisms of action

Data for 2-drug initial or maintenance therapy

What the future may hold…

*At least 3 new meds likely coming by early 2018!

Current State of ART

Recommended Initial ART Regimens

Sources:

2017 HHS Adult & Adolescent Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

2016 IAS-USA Antiretroviral Therapy Guidelines. IAS-USA. (www.iasusa.org)

HHS Guidelines (October 2017)

“Recommended for Most People”

Dolutegravir/ABC/3TC

Dolutegravir + TDF/FTC

Dolutegravir + TAF/FTC

Elvitegravir/Cobicistat/TDF/FTC

Elvitegravir/Cobicistat/TAF/FTC

Raltegravir + TDF/FTC

Raltegravir + TAF/FTC

IAS-USA Guidelines (July 2016)

“Recommended”

Dolutegravir/ABC/3TC

Dolutegravir + TAF/FTC

Elvitegravir/Cobicistat/TAF/FTC

Raltegravir + TAF/FTC

The Integrase Inhibitor Era

Superiority of Integrase Strand Transfer Inhibitors (INSTI’s)

Sources: adapted from a talk by Dr. Joe Eron at ID Week 2017 and other sources,

including Davy-Mendez T et al. JAIDS, Oct 2017 & Nance R et al. ID Week 2017.

INSTITreatment-Naïve

Study

Comparator

Anchor

Virologic

Efficacy

DolutegravirSINGLEFLAMINGOARIA (♀)

EfavirenzDarunavir/rAtazanavir/r

*88% vs 81%*90% vs 83%*82% vs 71%

ElvitegravirStudy 102Study 103WAVES (♀)

EfavirenzAtazanavir/rAtazanavir/r

88% vs 84%90% vs 87%*87% vs 81%

Raltegravir ACTG 5257Darunavir/r Atazanavir/r

*93.9% vs 89.4% vs 88.3%

Also reduced virologic failures, resistance, & regimen changes with INSTI’s

*Statistically significant difference

The “Should We Switch to TAF?” Era

Tenofovir DF (TDF) versus Tenofovir alafenamide (TAF)

Lymphoid CellsGut Plasma

TFV

TFV-MP

TFV-DP

TDF = tenofovir disoproxil fumarate; TFV = tenofovir

TDF TDF

P

P

TFV

Active drug

TAF TAFTAF

Cathepsin A

91% lower plasma TFV

levels with TAF

Tenofovir alafenamide (TAF) Summary

• Does TAF have virologic efficacy similar to TDF?

YES

• Does TAF have better side effect profile than TDF?

Renal proximal tubule wasting & bone mineral density: YES

Lipids: NO

• Is TAF safe with mild-moderate renal impairment?

YES: studied with CrCl 30-69 ml/min

• Does TAF have adequate activity against hepatitis B?

YES: approved by FDA for hepatitis B treatment

• What are we missing?

Long-term clinical outcomes data. PrEP & PEP data.

Tenofovir Alafenamide (TAF) and Tenofovir DF

Fixed-Dose Preparations

Source: photos taken by speaker to show relative size difference.

TAF/FTC

(Descovy)

TDF/FTC

(Truvada)

RPV/TAF/FTC

(Odefsey)

RPV/TDF/FTC

(Complera)

ELV/c/TAF/FTC

(Genvoya)

ELV/c/TDF/FTC

(Stribild)

The Current State of ART

• High expected efficacy of first-line (mostly integrase) ART

• Frequent discussions about updating, simplifying, or

switching to improve quality of life and reduce toxicity/risk

• Therapy that is better tolerated, but still not perfect

- INSTI’s may cause CNS side effects (and weight gain??)

(see reviews at www.hivecho.org)

• Still many individuals who struggle with adherence

• Some with few remaining options due to resistance

http://www.hivecho.org/

Let’s Turn to the Future of ART…

Cabotegravir(INSTI)

Adapted from: HIV Pipeline Report 2017 and other sources

Phase I & II Late Phase (III & Beyond)

*Bictegravir(INSTI)

Cabotegravir(INSTI)

Rilpivirine-LA (NNRTI)

Doravirine(NNRTI)

*DRV/c/TAF/FTC(INSTI/NRTI’s)

*Ibalizumab(Monoclonal Ab/Entry inhibitor)

MK-8591/EFdA(NRTI)

Elsufavirine(NNRTI)

Sifuvirtide(Fusion inhibitor)

PRO-140 (Monoclonal Ab/Entry inhibitor)

Cenicriviroc(CCR5/CCR2 inhibitor)

VRC01(Broadly neutralizing Ab)

Fostemsavir(Attachment inhibitor)

*DTG/RPV(INSTI/NNRTI)

Albuvirtide(Fusion inhibitor)

DTG/3TC (INSTI/NRTI)

GSK-3640254(Maturation inhibitor)

GS-PI1(Protease inhibitor)

GS-CA1(Capsid inhibitor)

ABX464(Rev inhibitor)

Oral Parenteral

*FDA to review soon!

New meds from existing classes

Bictegravir (INSTI)

Can we do better than current options?

BIC/TAF/FTC vs. DTG + TAF/FTC as Initial Therapy

GS-1490: Design

Source: Sax PE, et al. Lancet HIV, 2017. Also IAS 2017, Paris. Abstract TUPDB0201LB.

Bictegravir/TAF/FTC(n = 320)

Dolutegravir + TAF/FTC(n = 325)

Study Design: Study 1490

• Background:

- Phase III, double-blind, active

controlled, randomized trial

conducted on multiple continents

- Primary endpoint: proportion

with HIV RNA <50 copies/mL at

48 weeks

• Enrollment Criteria:- Antiretroviral-naïve adults- HIV RNA ≥500 copies/mL- Chronic hep B/C allowed- eGFR ≥30 mL/min

48 weeks


GS-1490: Results

Week 48 Virologic Response (Intention-to-Treat Analysis)


8993

0

20

40

60

80

100

HIV

RN

A <

50

co

pie

s/m

L (

%)

Bictegravir/TAF/FTC Dolutegravir + TAF/FTC

No participant discontinued due to lack of efficacy in either arm

No treatment-emergent resistance to any study drug occurred


GS-1490: Results


Treatment Emergent Adverse Events >5% in Study 1490 Through 48 Weeks

Bictegravir/TAF/FTC(n = 320)

Dolutegravir + TAF/FTC(n = 325)

Headache, % 13 12

Diarrhea, % 12 12

Nausea, % 8 9

Fatigue, % 6 8

Arthralgia, % 5 3

Insomnia, % 5 4

Change in eGFR -7.3 mL/min* -10.3 mL/min

*BIC may cause less potent blockage of tubular secretion of creatinine than DTG

BIC/TAF/FTC vs. DTG/ABC/3TC for Initial Therapy

Study 1489: Background

Source: Gallant JE et al. Lancet, Aug 2017. Also IAS 2017, Paris. Abstract 5783.

Study Design: Study 1489

• Background:






48 weeks

• Enrollment Criteria:

- Antiretroviral-naïve adults

- HIV RNA >500 copies/mL

- eGFR >50 mL/min

- HLA-B*5701 negative

- No chronic hep B

BIC/TAF/FTC(n = 314)

DTG/ABC/3TC(n = 315)

48 weeks


Study 1489: Results



92.4 93.0

0

20

40

60

80

100

HIV

RN

A <

50

co

pie

s/m

L (

%)

BIC/TAF/FTC DTG/ABC/3TC

No treatment-emergent resistance to any study drug occurred


Study 1489: Results


Treatment Emergent Adverse Events >5% in Study 1489 Through 48 Weeks

BIC/TAF/FTC, %(n = 314)

DTG/ABC/3TC, %(n = 315)

Diarrhea 13 13

Headache 12 14

Nausea 10 23*

Fatigue 6 9

Arthralgia 4 6

Insomnia 5 6

Change in eGFR -10.5 mL/min# -10.8 mL/min

*AE’s leading to treatment discontinuation: 0 BIC/TAF/FTC, 4 DTG/ABC/3TC

#Change in eGFR, proximal tubulopathy markers, BMD, and lipids all similar


Study 1489: Conclusions

• Investigator conclusions:

- Initial therapy with BIC/TAF/FTC non-inferior to DTG/ABC/3TC

- BIC/TAF/FTC well tolerated with fewer GI side effects

• My interpretation:

- Advantage of BIC/TAF/FTC: potent INSTI in single tablet with TAF

- Need more data on BIC neuropsych AE’s compared to DTG

- TAF and ABC similar in terms of BMD, lipids, & renal changes


BIC/TAF/FTC

Future Directions

• Switch from boosted PI presented at ID Week

• Additional switch studies ongoing

• Study of 440 women will reach primary endpoint in early 2018

• Regulatory filing submitted to the FDA (February target)

Source: Gallant JE et al. IAS 2017, Paris.

Bictegravir (BIC)

Questions

• Interaction with cations? Yes

• Interaction with metformin? Less than DTG

- BIC increased metformin AUC 27%-39% and Cmax 27%1,2

- DTG increased metformin AUC 79% and Cmax 66%3

• Interaction with rifampin? Yes

• Available as a stand-alone tablet? No

• How will this fit into clinical practice?

1. Zhang H et al. 18th Workshop on Clinical Pharmacology of ART, Chicago 2017.

2. Custodio J et al. ID Week, 2017. 3. Song IH et al. JAIDS, Aug 2016.

New meds from existing classes

Doravirine (NNRTI)

DOR/TDF/3TC vs. EFV/TDF/FTC for Initial Therapy

DRIVE AHEAD: Background

Source: Squires KE et al. IAS 2017, Paris. Abstract TUAB0104LB.

Study Design: DRIVE AHEAD

• Background:






48 weeks



- HIV RNA >1,000 copies/mL

- No genotypic resistance

- Chronic hep B/C allowed

DOR/TDF/3TC(n = 364)

EFV/TDF/FTC(n = 364)

48 weeks


DRIVE AHEAD: Results



8491

8181

91

81

0

20

40

60

80

100

All ≤100,000 copies/m >100,000 copies/mL

HIV

RN

A <

50

co

pie

s/m

L (

%)

Baseline HIV RNA

DOR/TDF/3TC EFV/TDF/FTC




Treatment Emergent Adverse Events >5% in DRIVE AHEAD Through 48 Weeks

DOR/TDF/3TC, %(n = 364)

EFV/TDF/FTC, %(n = 364)

Study drug-related AE’s 31 63*

Discontinued due to drug-related AE 2 6

Headache 13 12

Diarrhea 11 14

Nausea 8 11

Rash 5 12




Proportion with Pre-Defined Neuropsychiatric Side Effects at Week 48


8.8

12.1

4.4 4.1

37.1

25.5

8.26.6

0

10

20

30

40

*Dizziness *Sleep disorder,disturbance

*Alteredsensorium

Depression,suicide, self-injury

Perc

en

t o

f p

art

icip

an

ts

DOR/TDF/3TC EFV/TDF/FTC



DRIVE AHEAD: Conclusions

• Investigator conclusions:

- DOR/TDF/3TC non-inferior to EFV/TDF/FTC

- Lower rates of dizziness and sleep disorders; lipid effects better

• My interpretation and how it may fit into clinical practice:

- DOR has some advantages over existing NNRTI’s

• No food requirement, PPI’s ok, effective at any baseline HIV RNA level, once-daily dosing, active against common NNRTI mutations

• Need more data on mental health side effects

- Limitations: combined with TDF; compared to EFV and DRV/r


Other New Formulations and Dosages

• Darunavir/cobi/TAF/FTC (“Symtuza”)

- EMERALD: switch from boosted PI + TDF/FTC maintains virologic

suppression and improves bone mineral density1

- AMBER: as effective as darunavir/cobi + TDF/FTC for initial ART2

• Raltegravir high-dose once-daily (“RAL-HD”)

- ONCEMRK: two 600 mg tabs once-daily equivalent to 400 mg BID

(each given with daily TDF/FTC)3

Sources: 1. Orkin C et al. Lancet HIV, Oct 2017. 2. Gallant J et al. European AIDS Conference,

Oct 2017. 3. Cahn P et al. Lancet HIV, Sept 2017.

New Meds from Existing Classes

(also Dual Maintenance ART)

IM Cabotegravir + IM Rilpivirine-LA

Let’s talk about injectables!

Cabotegravir IM + Rilpivirine IM versus Cabotegravir + ABC/3TC

LATTE-2: Design

Source: Eron JJ et al. IAS 2017, Paris. Abstract 5628. Margolis DA et al. Lancet. July 2017.

CAB 30 mg PO QD

+ ABC/3TC

CAB 400 mg IM Q4w +

RPV 600 mg IM Q4w(n = 115)

CAB 600 mg IM Q8w +

RPV 900 mg IM Q8w(n = 115)

CAB 30 mg PO QD +

ABC/3TC(n = 56)

Continued to maintenance phase if

HIV RNA <50 copies/mL from weeks 16-20

Lead-In Phase Maintenance PhaseStudy Design:

• Background: Phase 2b,

randomized, open-label trial

assessing dual therapy with

long-acting, injectable agents

for maintenance

• Inclusion Criteria


- HIV RNA >1,000 copies/mL

- CD4 count >200 cells/mm3

- CrCl >50 mL/min

- No major drug resistance

mutations, pregnancy,

significant hepatic impairment,

or AIDS defining condition

16 20Week

RPV PO Added

96 weeks


LATTE-2: Results


8794

84

0

20

40

60

80

100

CAB 400 mg IM Q4w +RPV 600 mg IM Q4w

CAB 600 mg IM Q8w +RPV 900 mg IM Q8w

CAB 30 mg PO +ABC/3TC PO

HIV

RN

A <

50 c

op

ies/m

L



LATTE-2: Results


LATTE-2 Study Week 96 Virologic Response

IM CAB/RPV q4 weeks(n = 115)

IM CAB/RPV q8 weeks(n = 115)

Oral CAB+

ABC/3TC(n = 56)

Virologic response 100 (87%) 108 (94%) 47 (84%)

No virologic data 15 (13%) 2 (2%) 8 (14%)

Protocol-defined virologic failure - 2 (2%) 1 (2%)

Treatment-emergent resistance - Yes# No

#1 with INSTI resistance mixture that does not affect CAB activity;

1 with significant NNRTI and INSTI resistance (K103N, E138G, Q148R)


LATTE-2: Results

Treatment Emergent Adverse Events in LATTE-2 Through Week 96

IM CAB/RPV q4 weeks

(n = 115)

IM CAB/RPV q8 weeks

(n = 115)

Oral CAB + ABC/3TC

(n = 56)

Grade 1-4

Grade 3-4

Grade 1-4

Grade 3-4

Grade 1-4

Grade 3-4

Any event, % 98 9 96 9 38 2

Nausea, % 10 0 7 0 9 0

Headache, % 6 0 5 0 7 0

Pyrexia, % 6 0 4 0 0 0

Injection site pain, % 97 5 95 7

Injection site nodule, % 30 <1 25 <1

Injection site swelling, % 30 0 25 <1

Injection site pruritis, % 29 0 21 0

Injection site induration, % 22 0 24 0

Injection site bruising, % 12 0 17 0

Injection site erythema, % 17 0 10 0


IM Long-Acting Cabotegravir + Rilpivirine

• Future Directions:

- ATLAS: q4 week maintenance; enrolled and ongoing

- ATLAS-2M: q8 week vs q4 week maintenance; planned, not yet open

- FLAIR: switch from DTG/ABC/3TC to q4 week maintenance

• How will this fit into clinical practice?

- Improving adherence for the most challenging patients?

- Reducing stigma? Combatting pill fatigue? Improving care

transitions? Other?

www.clinicaltrials.gov

Agents with Novel Mechanisms of Action

Fostemsavir (Oral Entry Inhibitor)

Ibalizumab (IV Monoclonal Antibody Entry Inhibitor)

What about the individual with no remaining ART options?

Novel Entry Inhibitors: Fostemsavir

Fostemsavir

(blocks gp120 attachment)

Figure adapted with permission from: Gandhi M, Gandhi RT. N Engl J Med. 2014;371:248-59.

Novel Entry Inhibitors: Ibalizumab

Ibalizumab

(binds CD4 receptor)

Figure adapted with permission from: Gandhi M, Gandhi RT. N Engl J Med. 2014;371:248-59.

2-Drug Oral ART for

Initial or Maintenance Treatment

Can ART be simpler?

Why Study Dual ART?

• Potential to reduce side effects

• Reserve future options

• Cost saving!

- Assuming DTG + 3TC yields >90% efficacy:

• 50% uptake of maintenance or initial ART savings of

$550 & $800 million, respectively, over 5 years

• If 25% of currently suppressed persons switch to DTG +

3TC maintenance savings >$3 billion

Source: Girourard et al. CID, March 2016.

Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.

Dolutegravir + Rilpivirine Maintenance ART

SWORD Study: Background

Study Design: SWORD 1&2

• Background: Randomized, multinational, open-label, industry-sponsored, parallel-group, non-inferiority studies

• Inclusion Criteria:

- On stable 3-drug ART:

2 NRTI’s + INSTI, NNRTI, or

boosted PI for >6 months

- 1st or 2nd regimen with no prior

change due to virological failure

- HIV RNA <50 for >12 months

- No HBV co-infection

DTG + RPV

DTG + RPV(n = 513)

Continue

3-Drug ART(n = 511)

Primary endpoint: week 48 HIV RNA

<50 copies/mL by snapshot analysis

Early switch phase Late switch phase

48 weeks

Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.


SWORD Study: Results

95.0 95.0

50

60

70

80

90

100

% w

ith H

IV R

NA

<50 c

opie

s/m

L

DTG + RPV 3-Drug ART

2 virologic failures in each arm; 1 in DTG + RPV arm had K101K/E

(with HIV RNA >1 million copies/mL); no integrase resistance occurred)


SWORD Study: More Results & Conclusions

• Additional results:

- Overall neutral effect on lipids

- Significant improvement in bone mineral density & biomarkers

• Conclusions:

- DTG + RPV maintenance works for carefully selected persons

- Regulatory FDA filing for DTG/RPV (“Juluca”)

- How will this fit into clinical practice?

Sources: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.

McComsey G et al. IAS, Paris 2017.

Dolutegravir plus Lamivudine for Initial Therapy

ACTG 5353: Background

Source: Taiwo BO et al. IAS 2017, Paris. Abstract 5634.

Study Design: ACTG 5353

• Background:

- Phase II, single-arm, pilot study

to assess virologic efficacy of

DTG + 3TC as initial ART

- Motivated by PADDLE, in which

18/20 participants obtained

virologic suppression at week 48



- HIV RNA >1,000 copies/mL and

<500,000 copies/mL

- No evidence of NRTI, integrase,

or major PI resistance mutations

- No chronic hep B

DTG + 3TC(n = 120)

24 weeks

n=83 with HIV RNA <100,000 copies/mL

n=37 with HIV RNA >100,000 copies/mL


ACTG 5353: Results



90 89 90

0

20

40

60

80

100

All ≤100,000 copies/m >100,000 copies/mL

HIV

RN

A <

50

co

pie

s/m

L (

%)

Baseline HIV RNA

3 participants had virologic failure, 1 with emergent M184V and R263R/K mixture


ACTG 5353: Conclusions

• Investigator Conclusions:

- DTG + 3TC demonstrated potent virologic efficacy with study entry

viral load up to 500,000 copies/mL

- Virologic failure uncommon and associated with suboptimal adherence

- Future: GEMINI 1&2 studies

• Questions and how this may fit into clinical practice:

- Risk of resistance with suboptimal adherence? Efficacy in CNS &

other compartments? Necessity in the current ART era?


Is Dual ART the Future?

Ongoing Trials (Selected List)

• Initial ART

- DTG + 3TC (ACTG 5353, GEMINI)

- DRV/r + 3TC (ANDES)

- DRV/cobi + RPV (PREZENT)

Source: clinicaltrials.gov

• Maintenance ART

- IM CAB + IM RPV-LA (ATLAS, FLAIR)

- DRV/r + DTG (DUALIS)

- DTG + RPV (SWORD1&2)

- DTG + 3TC (LAMIDOL, ASPIRE)

- DRV/r + 3TC (DUAL GESIDA)

ART Monotherapy

Stop! Don’t Do It!

• DOLUMONO

- Suppressed individuals switched to DTG mono ART

- Stopped at 48 weeks (98% vs. 92% suppressed, p=0.03)

- 9 virologic failures with DTG (3 with resistance)

• MOBIDIP

- Suppressed individuals taking LPV/r or DRV/r + 2 NRTI’s

- Randomized to boosted PI + 3TC dual or boosted PI mono ART

- More virologic failures with mono ART (24.8% vs 3.0%)

Sources: Wijting IAE, et al. Abstract 451LB. CROI 2017. Seattle, WA.

Ciaffi L et al. Lancet HIV, May 2017.

What Happens When TDF Becomes Generic???

Source: adapted from a talk by Rochelle Walensky at ID Week 2017, as well as

Walensky R et al, “The EpiTAF for TDF?” CID April 2016.

• No one knows! Lots of variables…

- 2-5 years for generic market competition to decrease costs

- Generics can’t be co-formulated in US

- May lower wholesale costs but what about copays? Adherence?

- If generic TDF+3TC+branded DTG available, TAF/FTC + DTG

must be <$35k/year to remain cost effective

- How will guidelines handle TDF? What about 340B revenue?

What the More Distant

Future May Hold

• Long-acting nanoformulations

• New drug-delivery systems

• Hopefully, long-acting agents

that are easy to administer

with low risk of resistance

• For now, continued efforts

to improve our strong,

albeit imperfect, arsenal

• And to improve implementation,

delivery, and adherence

Early Phase (I & II)

MK-8591/EFdA(NRTI)

Elsufavirine(NNRTI)

Sifuvirtide(Fusion Inhibitor)

Cenicriviroc(CCR5/CCR2 Inhibitor)

VRC01(Broadly neutralizing antibody)

GSK-3640254(Maturation inhibitor)

GS-PI1(Protease inhibitor)

GS-CA1(Capsid inhibitor)

ABX464(Rev inhibitor)

Acknowledgements & Questions

• Thank you to my many mentors at Madison Clinic and the

MW AETC, and to Carlos, Chris, and Julia for technical

support (and patience)

• Feel free to email questions or comments:

[email protected]

mailto:[email protected]

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