The Art of Antiretroviral Therapy Annie Luetkemeyer, MD Medical - - PDF document

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The Art of Antiretroviral Therapy Annie Luetkemeyer, MD Medical - - PDF document

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12/13/19 The Art of Antiretroviral Therapy Annie Luetkemeyer, MD Medical Management of AIDS and Hepatitis, 2019 1 Disclosure Research grant support to UCSF related to HIV treatment from: Gilead Merck Viiv 2 1 12/13/19 2019:

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The Art of Antiretroviral Therapy

Annie Luetkemeyer, MD Medical Management of AIDS and Hepatitis, 2019

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Disclosure

Research grant support to UCSF related to HIV treatment from:

  • Gilead
  • Merck
  • Viiv

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2019: What to start in “most patients” CLASS REGIMEN INSTI BIC/TAF/FTC INSTI DTG/ABC/3TC INSTI DTG/TAF/FTC INSTI* RTG/TAF/FTC*

*HHS Guidelines only

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When one size doesn’t fit all

  • Rapid start
  • High HIV RNA, low CD4 cell count
  • Switching- when to consider newer

regimens & what to when drug resistance present

  • Abacavir and tenofovir sparing regimens
  • Extensive resistance

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Case #1 : RAPID ART Start

48 year old man, new diagnosis of HIV, when admitted to hospital with community acquired pneumonia

  • CD4+ 275, HIV RNA 80,000 copies
  • HIV genotype and HLA-B*5701 both

pending

  • Comorbidities
  • HTN
  • Hyperlipidemia
  • Mild renal insufficiency, eGFR = 50

5

ARS: What do you recommend?

1) Start BIC/TAF/FTC now 2) Start DTG/3TC 3) Start DTG/RPV 4) Start DTG/ABC/3TC 5) Wait for HIV Genotype to return

New HIV diagnosis, CD4 275, HIV RNA 80K, No HIV genotype yet, mild renal insufficiency

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ARS: What do you recommend?

1) Start BIC/TAF/FTC now 2) Start DTG/3TC -> DTG monotherapy if 3TC resistance 3) Start DTG/RPV -> NO ART start data 4) Start DTG/ABC/3TC-> NO HLA-B*5701 5) Wait for HIV Genotype to return

New HIV diagnosis, CD4 275, HIV RNA 80K, No HIV genotype yet, mild renal insufficiency

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RAPID ART Start: Take homes

  • DO start ART ASAP: Both DHHS & IAS-USA

guidelines recommend ART initiation as soon as possible after diagnosis, if the patient is

  • pen to starting
  • DON’T wait for genotype/HLA-B5701 results

(but DO send!)

  • DON’T start two-drug regimens without

resistance data to guide you!

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Case #2: High HIV RNA & Low CD4+

58 year old man, new diagnosis of HIV with CD4+ 110, HIV RNA 425,000.

  • No evidence of opportunistic infection
  • Genotype = wild type
  • HLA-B*5701 negative
  • Renal insufficiency due to poorly controlled

diabetes and hypertension, eGFR=50

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Which tenofovir-sparing ART regimen is an option with a high viral load & low CD4+ cell count ?

1) Dolutegravir/rilpivine 2) Dolutegravir/3TC 3) Atazanavir/r plus ABC/3TC 4) DTG/ABC/3TC 5) Darunavir/r plus Raltegravir

CD4+ 110, VL 425K, eGFR=50 HIV genotype = wild type

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Which tenofovir-sparing ART regimen is an option with a high viral load & low CD4+ cell count?

1) Dolutegravir/rilpivine 2) Dolutegravir/3TC 3) Atazanavir/r plus ABC/3TC 4) DTG/ABC/3TC 5) Darunavir/r plus Raltegravir

CD4+ 110, VL 425K, eGFR=50 HIV genotype = wild type

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DHHS guidelines

AVOID with CD4+ < 200 Rilpivirine-containing regimens Higher rates of virologic failure

  • bserved

DRV/r + RAL AVOID with HIV RNA > 100,000 Rilpivirine-containing regimens Higher rates of virologic failure

  • bserved

ABC/3TC + EFV ABC/3TC + ATV/r DRV/R + RAL

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Caveats

  • CD4+ < 200
  • W48 HIV RNA not < 50: 2 drug: 79% (50/63) vs 3 drug 93% (51/55)
  • However, few failures due to HIV VL >50- 2 drug:3 vs 3 drug:1
  • Excluded VL > 500,000 at screening

Gemini Studies: DTG/3TC vs DTG+TDF/FTC in treatment-naïve

Cahn Lancet 2019, 393(10167):143-155

Take home: Caution with DTG/3TC with very high viral load & low CD4+ until more data.

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Case #3: ART of the Switch

38 year male body builder, travels extensively to compete, currently on his first regimen of BIC/TAF/FTC.

  • CD4+ 450, HIV RNA suppressed
  • Baseline genotype = wildtype

He is distressed by reports of weight gain with INSTI’s and TAF and would like to change regimens. He has been reading about ART options and has the following requests: 1) One pill daily 2) No food requirement 3) Absolutely cannot be associated with weight gain

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ARS:Which of these regimens meets his requirements?

1) Dolutegravir/Rilpivirine 2) Doravirine/TDF/3TC 3) Dolutegravir/3TC 4) Elvitegravir/cobicistat/TAF/FTC 5) BIC/TAF/FTC (current regimen)

Suppressed on BIC/TAF/FTC, HIV = wild type Requests:

ü single pill ü no food requirement ü no reported association with weight gain

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Which of these regimens meets his requirements?

1) Dolutegravir/Rilpivirine 2) Doravirine/TDF/3TC 3) Dolutegravir/3TC 4) Elvitegravir/cobicistat/TAF/FTC 5) BIC/TAF/FTC (current regimen)

Suppressed on BIC/TAF/FTC, HIV = wild type Requests:

ü single pill ü no food requirement ü no reported association with weight gain

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Food requirement ART Can be taken without regard to food

  • INSTI’s: BIC, DTG, RAL
  • NNRTI: DOR

Take with food

  • All cobi- and ritonavir-

boosted PI’s

  • NNRTI’s: RIL
  • INSTI: ELV/cobi

Take on empty stomach

  • NNRTI: Efavirenz

DHHS Guidelines 7/2019

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Doravirine

  • NNRTI approved in 8/2018
  • Both as stand alone pill &

DOR/TDF/3TC FDC

  • Can be given without regard

to food or acid suppression

  • Active against NNRTI

mutations K103N, Y181C, G190A

  • 2 treatment naïve studies & 1

switch study

www.i-Base.com (unbranded)

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DRIVE FORWARD: DOR + 2 NRTI equivalent to DRV/r + 2 NRTI

HIV-1 RNA < 50 c/mL HIV-1 RNA ≥ 50 c/mL No Data in Window Patients (%) 100 80 60 40 20 84 81

DOR/3TC/TDF (n = 364) EFV/FTC/TDF (n = 364)

11 10 5 9 Treatment difference: 3.5% (95% CI: -2.0% to 9.0%) No Data 100 80 60 40 20 Patients (%) 84 80 11 13 5 7 Treatment difference: 3.9% (95% CI: -1.6% to 9.4%)

DOR + 2 NRTIs (n = 383) DRV/RTV + 2 NRTIs (n = 383)

DRIVE-AHEAD: DOR + TDF/3TC equivalent to EFV/FTC/TDF

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Outcome DOR + 2 NRTIs (n = 383) DRV/RTV + 2 NRTIs (n = 383) DOR/3TC/TDF (n = 364) EFV/FTC/TDF (n = 364) PROTOCOL DEFINED FAILURE n (%) 34 (9) 43 (11) 34 (9) 28 (8) Successful resistance analysis § DOR resistance § NRTI resistance § PI resistance § EFV resistance 15 2 2

  • NA

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  • 1

NA 34 6 5 NA

  • 33
  • 5

NA 13 DRIVE FORWARD: DOR + 2 NRTI equivalent to DRV/r + 2 NRTI

HIV-1 RNA < 50 c/mL HIV-1 RNA ≥ 50 c/mL No Data in Window Patients (%) 100 80 60 40 20 84 81

DOR/3TC/TDF (n = 364) EFV/FTC/TDF (n = 364)

11 10 5 9 Treatment difference: 3.5% (95% CI: -2.0% to 9.0%) No Data 100 80 60 40 20 Patients (%) 84 80 11 13 5 7 Treatment difference: 3.9% (95% CI: -1.6% to 9.4%)

DOR + 2 NRTIs (n = 383) DRV/RTV + 2 NRTIs (n = 383)

DRIVE-AHEAD: DOR + TDF/3TC equivalent to EFV/FTC/TDF

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Doravine Switch study: DRIVE-SHIFT

Johnson JAIDS 2019 81(4): 463

  • Suppressed x ≥ 6 months
  • PI/r or PI/c, ELV/c, NNRTI plus 2 NRTI
  • No prior HIV virologic failure & DOR/3TC/TDF resistance exclusionary
  • Randomized to 24 weeks of continued therapy vs DOR/3TC/TDF then all on

DOR/3TC/TDF x 24 weeks

  • DOR/3TC/TDF 90.8% vs No switch 94.6%
  • 7 with protocol defined failure after switch,

none with DOR resistance.

  • 23 with baseline non-DOR NNRTI resistance

switched, 21 suppressed (2 discontinued)

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Doravirine

PRO’s

  • No food requirement
  • Data to support use in

treatment naïve

  • Vs.EFV/TDF/FTC
  • Vs. DRV/r + 2 NRTI
  • One switch study with

equivalence

  • NOT a PI or INSTI

CONS

  • No data in patients with

virologic failure or more heavily treatment experienced

  • NNRTI & NRTI resistance at

time of failure- lower barrier to resistance

  • No long term data - what

side effects will be discovered? Coformulated with TDF not TAF

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Case #4: NRTI free Switch

67 year old woman, HIV well controlled

  • n DRV/c/TAF/FTC with excellent adherence.
  • Known baseline M184V
  • HLA-B*5701(+)
  • Osteoporosis, on a bisphosphonate

You would like to change her off of tenofovir-containing ART given her osteoporosis & abacavir-containing regimens not an option

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ARS: Which 2 drug regimen is not recommended as an ABC/TDF sparing

  • ption in the current DHHS guidelines?

1) Dolutegravir/3TC 2) Darunavir/r + Raltegravir 3) Darunavir/r + 3TC 4) Cabotegravir/Rilpivirine

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ARS: Which 2 drug regimen is not recommended as an ABC/TDF sparing

  • ption in the current DHHS guidelines?

1) Dolutegravir/3TC 2) Darunavir/r + Raltegravir 3) Darunavir/r + 3TC 4) Cabotegravir/Rilpivirine ( under FDA review)

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NRTI-sparing Switch options

3TC-containing DTG/3TC

LAMIDOL, ASPIRE, TANGO

DRV/r +3TC

DUAL GESIDA, DUALIS

ATV/r + 3TC

ATLAS-M, SALT

3TC- sparing DTG/RPV

SWORD

DTG + DRV/r

DUALIS

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NRTI-sparing Switch options

3TC-containing DTG/3TC

LAMIDOL, ASPIRE, TANGO

DRV/r +3TC

DUAL GESIDA, DUALIS

ATV/r + 3TC

ATLAS-M, SALT

3TC- sparing DTG/RPV

SWORD

DTG + DRV/r

DUALIS

Known M184V

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Switch to DTG/RPV: SWORD

  • HIV suppressed x > 6 months on 1st or 2nd ART

regimen (NNRTI, PI, INSTI + 2 NRTI)

  • Virologic failure
  • 3 DTG/RIL: 1 with resistance testing available
  • Mutations: No INSTI, 1 NNRTI K101K/R, resuppressed on DTG/RIL
  • Llibre. Lancet. 2018;391:839.
  • Libre. Lancet. 2018;391:839.

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DTG/RIL

PRO’s

  • Single tablet
  • One switch study with

equivalence

  • Tenofovir & Abacavir

sparing CONS

  • Food requirement
  • Avoid acid blockers
  • No data for treatment

initiation

  • Avoid with HBsAg(+)

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Sw Switch to to bo boosted d DR DRV/DTG from m bo boosted d DR DRV + + 2 NR NRTIs: : DU DUALI LIS

  • Spinner. IAS 2019. Abstr MOPEB269

Inclusion Criteria § bDRV + 2 NRTIs for at least 24 weeks § HIV-1 RNA < 50 at screening § No known DRV or INSTI resistance § Prior regimens permitted § Hepatitis B negative

bDRV + DTG (n = 131) bDRV + 2 NRTIs (n = 132)

86% 88%

  • DTG/boosted DRV NON inferior to

boosted DRV + NRTIS

  • No treatment emergent resistance in

either arm

  • No difference by baseline CD4 < or > 200

Week 48 data

Spinner IAS 2019

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Future IM NRTI sparing option? Cabotegravir & Rilpivirine:

  • ATLAS & FLAIR studies
  • FLAIR: ART “naïve” (DTG/ABC/3TC x 20 weeks first)
  • ATLAS: On PI, NNRTI, INSTI + 2 NRTIs (1st or 2nd regimen)
  • Interventions: Oral CAB/RIL x 4 weeks, then monthly IM

injections

Overton IAS 2019 Abstr MOPEB257

Injection Site reactions by week Week 48 data

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At time of virologic failure:

  • All with NNRTI resistance
  • 4/6 with INSTI resistance

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IM CAB + RIL

PRO’s

  • No food requirement

(after lead in)

  • Once monthly dosing
  • May be good option for

those with adherence challenges if regularly engaged

  • Tolerated well by those

who have chosen injectable ART CONS

  • Injections may not

acceptable to many patients

  • Very long half life: risk for

drug resistance if ART stopped

  • Virologic failures: INSTI &

NNRTI resistance

  • Oral lead-in required to

ensure tolerance

  • No data for starting de novo

in viremic patients

  • Challenges of programmatic

implementation

  • Avoid in HBsAg (+)

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Case #5 Drug resistance

56 year old women with substantial prior treatment experience, intermittent poor adherence and now HIV resistance. Transferring her care to you. Prior regimens include:

  • EFV/TDF/3TC
  • Atazanavir/r + AZT/3TC/ABC
  • Elvitegravir/c/TDF/FTC

Currently on Darunavir/c/TAF/FTC plus DTG BID, CD4+ 250, VL 12K. She reports intermittent adherence due to GI intolerance and strongly prefers a PI sparing regimen

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Salvage Landscape

  • Fusion inhibitors: Ibalizumab (IV q 2 weeks) and

enfuvirtide (SubQ)

  • Fostemsavir:
  • Oral GP120 attachment inhibitor
  • Submitted for US FDA approval 12/5/19

BRIGHTE Study Fostemsavir 600 BID plus Optimized Background Ø Randomized cohort: ≥ 1 ART class that is fully active : 54% suppression Ø Non-Randomized cohort: ZERO remaining active agents: 38% suppression

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Salvage take homes

  • Don’t forget the drugs we do have
  • Maraviroc (requires Trofile testing)
  • T20 and Ibalizumab- for highly motivated patients
  • Beware INSTI resistance, particularly with prior RAL

& Elvitegravir use (or DTG monotherapy…)

  • Pipeline of new drugs does exist
  • Fostemsavir – potential approval in 2020
  • MK-5891 (islatravir, NRTTI) plus Doravirine- potential use

in salvage regimens (PO)

  • Capsid inhibitor (long acting, SubQ)
  • Broadly neutralizing antibodies (bNAbs) – IV infusion

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Summary

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Summary

2 drug therapy: lots of choices!

  • Not for rapid start
  • Caution with suboptimal

adherence

  • Test for HBV!
  • More data for low CD4, high VL

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Summary

2 drug therapy: lots of choices!

  • Not for rapid start
  • Caution with suboptimal

adherence

  • Test for HBV!
  • More data for low CD4, high VL

Doravirine as a new PI/INSTI sparing option Welcome longer term data on side effects & drug resistance

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Summary

2 drug therapy: lots of choices!

  • Not for rapid start
  • Caution with suboptimal

adherence

  • Test for HBV!
  • More data for low CD4, high VL

Doravirine as a new PI/INSTI sparing option Welcome longer term data on side effects & drug resistance Cabotegravir/Rilpivirine: NRTI sparing, IM regimen Patients who may need this regimen the most are at highest risk for resistance

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Summary

2 drug therapy: lots of choices!

  • Not for rapid start
  • Caution with suboptimal

adherence

  • Test for HBV!
  • More data for low CD4, high VL

Doravirine as a new PI/INSTI sparing option Welcome longer term data on side effects & drug resistance Cabotegravir/Rilpivirine: NRTI sparing, IM regimen Patients who may need this regimen the most are at highest risk for resistance New drug pipeline including salvage drugs How and when to best use

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Acknowledgments

  • Monica Gandhi
  • Diane Havlir
  • Susa Coffey
  • Brad Hare
  • Vivek Jain
  • Harry Lampiris
  • Meg Newman

In Memoriam Rakesh Mishra, 2019

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