crafting an art regimen for initiation or salvage: are...

NORTHWEST AIDS EDUCATION AND TRAINING CENTER

Crafting an ART Regimen for Initiation or Salvage: Are NRTI’s Necessary? Brian R. Wood, MD Assistant Professor of Medicine, University of Washington Medical Director, NW AETC ECHO

Last Updated: 1/22/15

NRTI-Sparing Regimens: Outline

•  Treatment initiation •  Switching for maintenance •  Salvage therapy •  Future questions and directions

Why Consider NRTI-Sparing Regimens?

•  NRTI’s are the backbone of first-line and salvage regimens •  However, toxicity can be limiting

- Tenofovir à renal and bone effects - Abacavir à hypersensitivity if B*5701(+), ?CV effects - Older NRTI’s à many short and long-term side effects

•  Resistance may preclude use

Data for Use as Initial Therapy NRTI SPARING-REGIMENS

PI-Containing Dual Regimens for Initial Therapy

Study NRTI-Sparing Regimen

Comparator N Follow-up Efficacy Outcomes and Issues

NEAT/ ANRS 143

DRV/r + RAL

DRV/r + 2 NRTI’s

805 96 weeks Non-inferior

More failures and resistance if CD4 <200 or VL >100K

RADAR DRV/r + RAL

DRV/r + 2 NRTI’s

83 48 weeks Inferior More failures and treatment discontinuations

ACTG 5262 DRV/r + RAL

None 112 96 weeks High rate of failure (26%)

High rates of RAL resistance if VL >100K

PROGRESS LPV/r + RAL

LPV/r + 2 NRTI’s


Few participants with VL >100K

SPARTAN ATV (300 mg BID) + RAL

ATV/r + 2 NRTI’s

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.

PI-Containing Dual Regimens for Initial Therapy



ACTG 5142 LPV/r + EFV

LPV/r + 2 NRTI’s or EFV + 2 NRTI’s

757 112 weeks Non-inferior More resistance, hyperlipidemia

MODERN DRV/r + MCV (150 mg daily)

DRV/r + 2 NRTI’s


Inferior More failures, especially if VL >100K

MIDAS DRV/r + MCV (150 mg daily)

None 25 96 weeks Failure rate 16.7% at 48 weeks

More failures if VL >100K

A4001078 ATZ/r + MCV (150 mg daily)

ATZ/r + TDF-FTC

121 48 weeks Non-inferior More low-level viremia, more hyperbilirubinemia, not fully powered

ACTG 5142: Mugavero MJ et al. J Acquir Immune Defic Syndr. 2011 Nov 1;58(3):253-60. MODERN: Stellbrink HJ et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract TUAB0101. MIDAS: Taiwo B et al. 19th International AIDS Conference: Abstract TUPE099. A4001078: Mills A et al. JAIDS. 2013 Feb 1;62(2):164-70.

“NRTI-Lite” Regimens for Initial Therapy


Comparator N Follow-up Efficacy Issues

GARDEL LPV/r + 3TC

LPV/r + 2 NRTI’s


Comparator NRTI’s mostly AZT & 3TC

ACTG 5303 DRV/r + MVC (150 mg daily) + FTC

DRV/r + TDF/FTC

254 Ongoing…

GARDEL: Cahn P et al. 14th European AIDS Conference. Brussels; Sept. 2013. Abstract LBPS7/6. ACTG 5303: https://clinicaltrials.gov/ct2/show/NCT01400412

NRTI-Sparing or “Lite” Regimens for Initial Therapy: Summary

•  Studies limited by unusual dosing, outdated comparators, insufficient power, and other issues

•  Most studies show lower efficacy or more side effects without improving pill burden or dosing frequency

•  Two trials with the most reassuring results used boosted lopinavir, which is no longer a recommended agent

•  Need well-designed trials of modern drugs! -  ie. boosted darunavir + dolutegravir +/- 3TC/FTC

Data for Use as Maintenance Therapy NRTI SPARING-REGIMENS

New Data from IAS 2014 Switching to 2-Drug Regimen for Maintenance



SALT ATZ/r + 3TC

ATZ/r + 2 NRTI’s


OLE LPV/r + 3TC or FTC

LPV/r + 2 NRTI’s


HARNESS ATZ/r + RAL

ATZ/r + 2 NRTI’s


Inferior More virological rebound and low-level viremia

MARCH MVC (150 mg BID) + boosted PI

MVC (300 mg BID) + 2 NRTI’s

560 Ongoing…

SALT: Perez-Molina JL et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract LBPE 18. OLE: Gatell JM et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract LBPE17. HARNESS: Van Lunzen J et al. 20th International AIDS Conference; July 2014; Melbourne. Abstract LBPE19. MARCH: https://clinicaltrials.gov/ct2/show/NCT01384682

Data for Use as Salvage Therapy NRTI SPARING-REGIMENS

NRTI-Sparing Regimens for Salvage Therapy Randomized Trials

Study ART History

NRTI-Sparing Regimen

Comparator N F/u Efficacy Issues

OPTIONS PI failure >2 active agents, no NRTI’s

>2 active agents + NRTI’s

360 48 weeks

Non-inferior

Greater mortality in NRTI arm; only powered to detect 15% non-inferiority

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

OPTIONS: Tashima K et al. 20th CROI. Atlanta, March 2013. Abstract 153LB. 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.

NRTI-Sparing Regimens for Salvage Therapy Observational Studies

Study ART History

NRTI-Sparing Regimen

Comparator N F/u Efficacy Outcomes and Issues

Imaz et al. 2011

Triple-class failure

>2 active agents, no NRTI’s

>2 active agents, + NRTI’s

122 48 weeks

Non-inferior

INROADS Failing or naïve with resistance

DRV/r + ETR

None 54 48 weeks

100% VL suppressed (failing); 87% (naïve)

75% study completion; 2 acquired ETR resistance

Nozza et al. 2011

Triple class failure or resistance

RAL + ETR + MVC (all BID)

None 28 96 weeks

96% VL <50 copies

Imaz et al. 2009

Triple class resistance

RAL + ETR + DRV/r (all BID)

None 32 24 weeks

94% VL<50 copies

Imaz et al. J Antimicrob Chemother. 2011 Feb;66(2):358-62. INROADS: Ruane P et al. 7th IAS Conference. Kuala Lumpur, Malaysia. July 2013. Abstract WEPE515. Nozza et al. JAIDS. 2011 April;56(4):e113-e115. Imaz et al. J Acquir Immune Defic Syndr. 2009 Nov 1;52(3):382-6.

Should Cost Be a Consideration?

•  VERITAS (Trottier et al, Nov 2014): - 31 subjects with MDR HIV, on >4 ARV’s (w/1 inactive NRTI) - 3TC or FTC removed in 29 (94%); AZT or TDF in others - 1 or 2 ARV removals à mean annual savings of $3319 CDN or

$8630 CDN respectively

VERITAS: Trottier L et al. J Int AIDS Soc. 2014; 17(4Suppl 3): 19815.

Future Questions and Directions

•  Will we worry so much with tenofovir alafenamide (TAF)? •  What about dolutegravir? Need data for the following:

- Dolutegravir + boosted PI (+/- 3TC or FTC) - Rilpivirine + boosted darunavir + dolutegravir

•  How might cabotegravir (GSK-744) or rilpivirine-LA fit in?

NRTI-Sparing Regimens Take Home Points

•  Most data for initial therapy is limited by design/dosing issues •  Dual therapy options should be used only in unique cases

and perhaps for maintenance in select patients •  Anecdotally, “NRTI-lite” regimens like 3TC/FTC + boosted PI

+ integrase seem to work well, but we need data •  More advanced HIV disease equates to higher risk of failure •  Could consider including NRTI’s for salvage, at least until

suppressed, then simplify

Case Question

•  A patient previously treated with multiple NRTI’s, efavirenz, and boosted lopinavir transfers care to you. He has been off ART and viral load is 9,400. Prior genotypes show K103N, E138A, M184V, M41L, T215Y, K219Q, and PI mutations (but no darunavir-associated mutations).

•  He has never taken integrase inhibitors. You plan to restart ART with boosted darunavir, etravirine, and dolutegravir.

•  Would you add lamivudine (3TC) or emtricitabine (FTC)? A)  Yes, would add indefinitely B)  Yes, would add until viral load suppressed then withdraw C)  No, would not add

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