dual antiretroviral therapy (art): what do we...

This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice

related to any specific patient.

Mountain West AIDS Education and Training Center

Dual Antiretroviral Therapy (ART):

What Do We Know?

Brian R. Wood, MD

Assistant Professor of Medicine, University of Washington

Medical Director, MW AETC ECHO

Last Updated: 9/29/16

Dual ART: Outline

• Data for initial therapy

• Data for maintenance and salvage therapy

• Ongoing clinical trials

Why Is This Important?

• Dual ART may:

- Minimize toxicity

- Reduce cost

- Preserve future options

Data for Use as Initial TherapyDUAL ART

What’s In The HHS Guidelines?

• “Other regimens to consider for initial therapy if TAF, TDF,

and ABC cannot be used…”

- DRV/r + RAL (only if HIV RNA <100K and CD4 >200) [CI]

- LPV/r + 3TC (BID) [CI]

• When might this be considered?

- Renal insufficiency plus contraindication to ABC

Source: aidsinfo.gov; HHS Adult and Adolescent Treatment Guidelines

Boosted PI + Raltegravir

Dual Regimens for Initial Therapy

Study Dual ART

Regimen

Comparator N Follow-up Efficacy Outcomes and Issues

NEAT/

ANRS 143

DRV/r +

RAL

DRV/r +

TDF/FTC

805 96 weeks Non-

inferior

More failures and

resistance if CD4 <200;

trend toward more

failures if VL >100K

RADAR DRV/r +

RAL

DRV/r +

TDF/FTC

83 48 weeks Inferior Virologic efficacy 62.5%

dual vs 83.7% triple ART

ACTG 5262 DRV/r +

RAL

None 112 96 weeks 26%

failure

High rates of RAL

resistance if VL >100K

PROGRESS LPV/r +

RAL

LPV/r +

TDF/FTC

206 96 weeks Non-

inferior

Few participants with VL

>100K

SPARTAN ATV (300

mg BID) +

RAL

ATV/r +

TDF/FTC

94 Stopped at

24 weeks

Inferior More failures with

resistance and more

jaundice

NEAT/ANRS143: Raffi F et al. Lancet. 2014;384:1942-51. RADAR: Cutrell JM et al. PLoS One. 2014 Aug 29;9(8):e106221.

ACTG 5262: Taiwo B et al. AIDS. 2011;13;25(17):2113-22. PROGRESS: Reynes J et al. AIDS Res Hum Retroviruses. 2013

Feb;29(2):256-65. SPARTAN: Kozal MJ et al. HIV Clin Trials. 2012 May-Jun;13(3):119-30.

Boosted PI + Maraviroc

Dual Regimens for Initial Therapy

Study Dual ART

Regimen

Comparator N Follow-up Efficacy Outcomes and

Issues

MODERN DRV/r +

MVC (150

mg daily)

DRV/r +

TDF/FTC

797 Stopped at

48 weeks

Inferior Efficacy 77.3% dual

vs 86.8% triple ART

MIDAS DRV/r +

MVC (150

mg daily)


failures

Failures had baseline

HIV RNA >100K

A4001078 ATV/r +

MVC (150

mg daily)

ATZ/r +

TDF-FTC

121 48 weeks Non-inferior More low-level

viremia, more

hyperbilirubinemia,

not fully powered

MODERN: AIDS. 2016;30(8):1229-38. MIDAS: Taiwo B et al. JAIDS. 2013;64(2):167-176. A4001078: Mills A et al. JAIDS.

2013;62(2):164-70.

Boosted PI or DTG + 3TC for Initial Therapy

Study Dual ART

Regimen

Comparator N Follow-

up

Efficacy Issues

GARDEL LPV/r +

3TC (BID)

LPV/r +

2 NRTI’s

426 48 weeks Non-inferior High pill burden, LPV

no longer

recommended,

comparator NRTI’s

mostly AZT & 3TC

PADDLE DTG +

3TC

None 20 48 weeks 18/20

(90%) VL

<50 copies

Small study, tried to

exclude baseline VL

>100K; ACTG 5353

now recruiting (aim =

120 participants)

GARDEL: Cahn P et al. 14th European AIDS Conference. Brussels; Sept. 2013. Abstract LBPS7/6. PADDLE: Cahn P et al. AIDS

July 2016, Durban, late breaker abstract FRAB0104LB.

Dual ART for Initial Therapy

Interpretation

• Boosted PI + raltegravir: data very mixed; clearly not

reliable if advanced infection…use with caution

• Boosted PI + maraviroc: clearly inferior and not reliable

• Boosted PI or DTG + 3TC: seems to work?? potential cost-

saving future option??

Data for Use as Maintenance or Salvage

Therapy

DUAL ART

Switch to Boosted PI + Raltegravir or Maraviroc

*Participants Very Carefully Selected

Study Dual ART

Regimen


Issues

SPARE DRV/r +

RAL

LPV/r +

TDF/FTC

58 48 weeks Non-

inferior

HARNESS ATV/r +

RAL

ATV/r +

2 NRTI’s

109 Stopped at

48 weeks

Inferior More virologic

rebound and low-

level viremia

MARCH MVC (150

mg BID) +

PI/r

MVC (300 mg

BID) or PI/r+

2 NRTI’s

560 48 weeks Inferior Inferior virologic

suppression with

dual ART

SPARE: Nishijima T et al. PLoS One. 2013;8(8):e73639. HARNESS: van Lunzen J et al. J Acquir Immune Defic Syndr.

2016;71(5):538-543. MARCH: Pett SL et al. Clin Infect Dis. 2016;63(1):122-32.

Switch to Boosted PI + 3TC for Maintenance

*Participants Very Carefully Selected

Study Dual ART

Regimen


Issues

SALT ATV/r +

3TC

ATV/r +

2 NRTI’s

286 48 weeks Non-

inferior

ATV no longer a first-

line agent

OLE LPV/r +

3TC (QD)

LPV/r +

2 NRTI’s

250 48 weeks Non-

inferior

LPV no longer a first-

line agent

Casado et al

(2014

research

letter)

DRV/r +

3TC


efficacy

Single-arm, open-

label study; larger

trial ongoing

SALT: Perez-Molina JL et al. Lancet Infect Dis. 2015;15(7):775-84. OLE: Arribas JR et al. Lancet Infect Dis. 2015;15(7):785-92.

Casado et al. J Int AIDS Soc. 2014;17(4 Suppl 3):19801.

Switch to DRV/r + RPV for Maintenance

The PROBE Study

• Italian Cohort

- Prospective, open-label, pilot study

- 60 patients with suppressed HIV RNA on PI/r + 2 NRTI’s

- Randomized to switch to DRV/r + RPV or continue

- Median 6 years on ART, median 3 prior regimens

- Equivalent viral suppression at 48 weeks

Maggiolo F et al. J Acquir Immune Defic Syndr. 2016;72(1):46-51.

Conclusion: “This approach constitutes an alternative for patients

experiencing [NRTI]-related toxicities.”

Switch to DTG + RPV for SalvageTivEdO (Tivicay plus Edurant Observational Cohort)

• Italian Cohort

- 132 treatment-experienced patients

- 12.1% RNA >50 copies/mL at baseline

- 43.2% at least one prior virologic failure

- 12.1% 1-class resistance, 20.5% 2-class, 10.6% 3-class

- All switched to dolutegravir + rilpivirine

Sterrantino G et al. 14th EU Meeting on HIV and Hepatitis. May 2016, Rome, Italy.

By week 24, subjects with HIV RNA >50 copies declined from

12.1% to 0.8%; those in whom no virus was detected increased

from 67.4% to 84.4%

Switch to Dual ART for Salvage Therapy

Randomized Trials

Study ART

History

Dual ART

Regimen

Comparator N F/u Efficac

y

Issues

SECOND-

LINE

NNRTI

failure

LPV/r +

RAL

LPV/r +

2 or 3

NRTI’s

541 48

weeks

Non-

inferior

Open-label,

genotype optional,

included AZT,

endpoint VL <200

EARNEST NNRTI

failure

LPV/r +

RAL then

LPV/r

LPV/r +

NRTI’s

1277 96

weeks

Dual

therapy

non-

inferior

More resistance

and less VL

suppression with

LPV/r monotherapy

SELECT

(ACTG

5273)

NNRTI

failure

LPV/r +

RAL

LPV/r + 2 or

3 NRTI’s

515 48

weeks

Non-

inferior

SECOND-LINE: Boyd MA et al. Lancet. 2013 Jun 15;381(9883):2091-9. EARNEST: Paton NI et al. N Engl J Med. 2014 Jul

17;371(3):234-47. SELECT: La Rosa AM et al. Lancet HIV. 2016;3(6):e247-58.

Dual ART for Maintenance or Salvage

Interpretation

• Combo of boosted PI or DTG + 3TC or RPV seems most

promising

• May be considered for select patients in unique

circumstances

• We need larger, well-designed trials of modern drugs!

Systematic Review and Meta-Analysis of Dual ART

• 21 studies (11 first-line, 10 switch)

• 2,478 individuals dual ART vs. 2,343 control (triple ART)

• “Dual therapy, especially with regimens excluding maraviroc,

could be safe and efficacious, particularly in patients with

baseline viral loads <100,000 copies/mL. However, dual therapy

seems to have a greater risk of selecting resistance mutations.”

Source: Achhra AC et al. Lancet HIV. 2016 Aug;3(8):e351-60.

Virologic failure

(RR)

AE leading to

discontinuation (OR)

Resistance

mutations (OR)

First-line 1.17 0.97 2.04*

Switch 1.14 0.55 2.47

Overall 1.13 0.73 2.11*

*Statistically significant

DTG + 3TC as Initial Therapy or Simplification

Cost Effectiveness Model

Source: Girouard MP et al. Clin Infect Dis. 2016;62(6):784-91.

Results: With 50% updake of either induction-maintenance or two-

drugs for ART-naïve patients, cost savings totaled $550 million and

$800 million respectively, within five years; savings reached greater

than $3 billion if 25% of currently suppressed patients were

switched to DTG + 3TC maintenance.

Future Questions and Directions

• Ongoing trials:

- DTG + 3TC as initial therapy (ACTG 5353)

- DRV/r + 3TC as initial therapy

- Simplification to DRV/r + DTG (DUALIS)

- Simplification to DTG + RPV (SWORD1&2)

- Simplification to DRV/r + RPV

- Simplification to DRV/r + 3TC

- Simplification to IM cabotegravir-LA + rilpivirine LA (LATTE)

Source: clinicaltrials.gov

Questions to Consider

• For whom should we consider dual ART?

• Are dual ART studies worth the effort/cost?

• What will it take for you to feel comfortable prescribing dual ART?

dual antiretroviral therapy (art): what do we...

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