Antiretroviral Therapy: Panel none Discussion Medical Management - - PDF document

12/9/17 1

Antiretroviral Therapy: Panel Discussion

Medical Management of HIV December 9, 2017 Panelists: Harry Lampiris, MD; Annie Luetkemeyer, MD; Carina Marquez, MD Moderator: Oliver Bacon, MD

disclosures

• none

Questions

• What to start in an ART-naïve, with/without labs
• What to start if M184V alone?
• INSTI resistance
• New uses for old(er) drugs (rilpivirine, atazanavir)?
• Using fewer than 3 drugs
• Initial ART in pregnant women
• How will might soon-to-arrive ARVS change your initial management
• Treatment modification for (multiple) comorbidities, de-

intensification

Qu Question: : in the era of “Test and Treat,” what re regimen would you choose for an ARV-na naïve e pa patien ent wi withou

• ut re

resistance testing available?

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Case 1.

• 24, female, newly HIV+ : Lab-based Ag/Ab (+), differentiation Ab(-),

HIV RNA 1.2 million c/mL

• CD4, sCr, HLA-B*5701, genotype, INSTI genotype all pending.
• Urine HCG(-); has an IUD
• No comorbidities

Case 1: panelists, which regimen(s) for ARV- naïve patient who wants test-and-treat?

• 1. Elvitegravir/cobi/FTC/TAF
• 2. Darunavir 800mg QD + ritonavir 100mg QD + FTC/(TAF or TDF)
• 3. Raltegravir 1200mg QD + FTC/(TAF or TDF)
• 4. Dolutegravir/abacavir/3TC
• 5. Dolutegravir + FTC/(TAF or TDF)
• 6. Rilpivirine/FTC/(TAF or TDF)
• 7. Dolutegravir + 3TC

Recommended initial ART regimens reclassified in DHHS OCT2017

• I. For most people with HIV

INSTI + 2 NRTIs

• 1. DTG/ABC/3TC if HLA-B*5701 negative
• 2. (DTG or RAL) + FTC/tenofovir
• 3. Elvitegravir/cobicistat/FTC/tenofovir

Recommended initial ART regimens reclassified in DHHS OCT2017

• II. For certain clinical situations

1. Boosted PI + 2 NRTIs

• In general, DRV preferred over ATV
• No distinction between boosting agents (rtv vs cobi)
• 2 NRTIs can be (FTC or 3TC) + (tenofovir or ABC)
• ABC only if HLA-B*5701 negative
• Boosted ATV + ABC/3TC only if HIV RNA<100,000 c/mL

2. NNRTI + 2 NRTIs

1. EFV + (FTC or 3TC) + tenofovir 2. RPV/FTC/tenofovir only if HIV RNA<100,000 c/mL and CD4>200 cells/mm3

3. INSTI + 2 NRTIs

1. RAL + ABC + (3TC or FTC) only if HLA-B*5701 negative and HI RNA<100,000 c/mL

4. If TDF, TAF and ABC cannot be used

1. DRV/r + RAL 400mg BID only if HIV RNA<100,000 c/mL and CD4>200 cells/mm3 2. LPV/r BID + 3TC BID

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Question: (How) does presence of M184V V affect your choice of initial ART? T? Case 2

• 30, MSM, lab-based Ag/Ab(+) differentiation Ab HIV-1(+) at his most

recent PrEP visit 3 weeks ago.

• Had heard about “French study” and was taking Truvada before and

after sex, with some of his partners. Stopped altogether after testing HIV(+)

• CD4 550 cells/mm3, HIV RNA 50,000 c/mL, sCr 0.9, Hepatitis B sAg(-),

HLA-B*5701(-)

• GT: M184M/V

Case 2: Panelists, Choice of initial therapy with M184V?

• 1. Dolutegravir/abacavir/3TC
• 2. Elvitegravir/cobicistat/FTC/(TAF or TDF)
• 3. Elvitegravir/cobicistat/FTC/(TAF or TDF) + DRV
• 4. Dolutegravir + FTC/(TAF or TDF)
• 5. Darunavir 800mg QD + ritonavir 100mg QD + FTC/(TAF or TDF)
• 6. Darunavir/cobi + FTC/(TAF or TDF)

DAWNING: DTG Effective Even With Partially Active Background Regimen

§ Randomized, open-label phase IIIb study in which pts in resource- limited settings with virologic failure

• n NNRTI + 2 NRTIs treated with

DTG + 2 NRTIs or LPV/RTV + 2 NRTIs (N = 627)

– Pts could not have primary resistance to INSTIs or PIs; pts required to receive 1 fully active NRTI – Baseline NRTIs: ZDV + 3TC, 40%; TDF + 3TC or FTC, 42%; TDF + ZDV, 12%; ABC + 3TC, 2%

Aboud M, et al. IAS 2017. Abstract TUAB0105LB. *Treatment difference: 13.8% (95% CI: 7.3% to 20.3%; P < .001)

HIV-1 RNA < 50 copies/mL, Wk 24 (ITT-E)

DTG + 2 NRTIs LPV/RTV + 2 NRTIs

Pts (%) 100 80 60 40 20

Overall* 82 69 74 55 2 84 73 < 2 n/N = 257/ 312 215/ 312 45/ 61 35/ 64 212/ 251 180/ 248 Fully Active NRTIs Slide credit: clinicaloptions.com

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Qu Ques estion(s): : Ho How do you inter erpret res esults of the e Ge GenoS

• Sure

Arch chive assay when they suggest resistance ce in a patient with an undetect ctable VL? Ho How comfortable e are e you with do dolut utegravir ps pseudomonotherapy py?

Case 3:

• 54 yo man, homeless, heterosexual but no sex in 25 years. Recently moved

to SF from LA

• HCV ab(+) GT1a/1b; TC 153, H29, L62, TG312; sCr 0.8, Sulfa allergy
• HIV(+) and on treatment since 1993. Prior regimens unknown, but reports

having undetectable VL “ever since since viral loads could be measured,” and CD4 never <200. No h/o OIs. Current VL <20, CD4=816

• Currently on DRV/ABC/3TC x 2 years “I take it as many times a week as I

can;” records from LA clinic state he takes it 3x/week. He says will only take QD regimen.

• GenoSure Archive: NRTI: M41L, D67N, M184M/V, L210W T215Y; NNRTI:

none; PI: K20R, M36I, I62V

Case 3: Virologic suppression on DTG/ABC/3TC with ABC and 3TC resistance mutations by DNA testing

• 1. DTG/ABC/3TC (1 QD)
• 2. DTG + FTC/TAF (2 QD)
• 3. DRV/Cobi + DTG (2 QD)
• 4. DTG + RPV (2 QD)
• 5. E/C/F/TAF + DRV (2 QD)
• 6. Something else

GenoSure Archive: NRTI: M41L, D67N, M184M/V, L210W T215Y; NNRTI: none; PI: K20R, M36I, I62V; INSTI: none

Qu Ques estion: : What ARVs to use in the setting of resistance ce to INS INSTIs Is and and NR NRTIs Is? ?

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Case 4:

• 31, MSM, HIV+ 2007, BL HIV RNA > 100,000; baseline GT= wild-type,

HLA-B*5701(-); nadir CD4 189

• EFV/FTC/TDF ->rash-> ATV/r + FTC/TDF-> jaundice, total Bili 9.0
• RAL + FTC/TDF with intermittent suppression until persistent viremia

in 5/2017: HIV RNA 4136 c/mL, CD4 244 cells/mm3

• GT RT: M184V, K65R; PI: none; INSTI: G140S, Q148H. Trofile = R5 virus

Audience: if you prescribe ART, have you encountered patients who developed INSTI- resistance on Raltegravir or Elvitegravir?

• 1. Yes
• 2. No

Case 4: panelists: which of the following would you include in a regimen for INSTI (G140S, Q148H) and NRTI (K65R, M184V) resistance:

• 1. dolutegravir 50mg BID
• 2. darunavir 600 BID + ritonavir 100 BID
• 3. darunavir 800 QD + ritonavir 100 QD
• 4. etravirine 200mg BID
• 5. etravirine 400mg QD
• 6. rilpivirine 25mg QD
• 7. FTC/TAF 1 tab QD
• 8. ABC/3TC 1 tab QD

Feel free to use coformulations if available

Qu Question: : What would you use/not use for r initial ART T in a woman diagnosed with HIV V dur during ng pr pregna egnanc ncy?

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Case 5: initial ART for pregnant woman

• 32 y.o. woman, B-HCG(+) 6 months ago, LMP 7 months ago
• HIV+ by Ag/Ab and differentiation Ab 4 days ago
• Last (-)HIV test: 6 months ago
• Wants to keep pregnancy
• HIV RNA pending, GT pending, CD4 count 420 cells/mm3, HLA-

B*5701(-)

• CrCl>60ml/min

Case 5: 1st line ART for pregnant woman, rapid start, 3rd trimester

• 1. Dolutegravir/abacavir/3TC
• 2. Dolutegravir + FTC/TAF
• 3. Raltegravir 400mg BID + FTC/TDF
• 4. Elvitegravir/cobi/FTC/TDF
• 5. Efavirenz/FTC/TDF
• 6. Atazanavir 300mg QD+ ritonavir 100mg QD + FTC/TDF QD
• 7. Darunavir 600mg BID + ritonavir 100mg BID + FTC/TDF

23

Antiretroviral Agents and Pregnancy

NRTI NNRTI PI Entry Inhibitor Integrase Inhibitor Preferred Abacavir/lamivudine OR Emtricitabine*/tenofovir Atazanavir/r3 Darunavir/r plus preferred 2-NRTI Raltegravir plus preferred 2- NRTI backbone Alternative Zidovudine/LamivudineZi Efavirenz OR Rilpivirine plus preferred 2- NRTI Lopinavir/r plus preferred 2-NRTI Dolutegravir plus preferred 2-NRTI Insufficient data in pregnancy Emtricitabine/tenofovir alafenamide (TAF/FTC) Do not use in pregnancy ABC/AZT/3TC as complete regimen; d4T, ddI Etravirine, Nevirapine Tipranavir, Fosamprenavir/ Indinavir/ Saquinavir/ Rttonavir alone, Nelfinavir Maraviro c, T20 Elvitegravir/co bicistat

*Or lamivudine.

1May be initiated after the first 8 weeks of pregnancy. Evidence of human fetal risk; Pregnancy Category D. 2Contraindicated with CD4+ counts >250/mm3 due to potential for liver toxicity. 3Theoretical concern for hyperbilirubinemia. 4Co-formulated with cobicistat/emtricitabine/tenofovir DF.

Note: no data on use of cobicistat in pregnancy and can not be recommended for ART-naïve pregnant women at this time.

• DHHS. http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf. Revision October 16, 2016.

§ Prospective cohort study in HIV-infected women in Botswana initiating ART with EFV/FTC/TDF vs DTG/FTC/TDF while pregnant (N = 5438)

Tsepamo: Birth Outcomes When Initiating First- line DTG vs EFV in Pregnancy

Slide credit: clinicaloptions.com Zash R, et al. IAS 2017. Abstract MOAX0202LB. Adverse Birth Outcomes, n (%) DTG (n = 845) EFV (n = 4593) aRR* (95% CI) Any § Severe 291 (34.4) 92 (10.9) 1606 (35.0) 519 (11.3) 1.0 (0.9-1.1) 1.0 (0.8-1.2) Stillbirth 18 (2.1) 105 (2.3) 0.9 (0.6-1.5) Neonatal death (< 28 days) 11 (1.3) 60 (1.3) 1.0 (0.5-1.9) Preterm birth (< 37 wks) § Very preterm (< 32 wks) 149 (17.8) 35 (4.2) 844 (18.5) 160 (3.5) 1.0 (0.8-1.1) 1.2 (0.8-1.7) SGA (< 10th percentile weight) § Very SGA (< 3rd percentile weight) 156 (18.7) 51 (6.1) 838 (18.5) 302 (6.7) 1.0 (0.9-1.2) 0.9 (0.7-1.2) *For DTG vs EFV; adjusted for maternal age, education, gravida.

§ Few first-trimester ART exposures (DTG, n = 116; EFV, n = 396); most second/third trimester § Only 1 major congenital abnormality observed (skeletal dysplasia in EFV-exposed group) § ABO risks similar when initiating first-line DTG vs EFV in pregnancy

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Qu Question: : It’s Decemb mber r 9, 9, 2018.

• 2018. How are you

th thin inkin ing ab about t usin ing new ARVs/tr trea eatm tmen ent t st strategies for treatment-na naïve e pa patien ents?

Case 6: new drugs/strategies for first line in 2018

• 51, newly confirmed HIV+ by CDC algorithm 2 weeks ago, last HIV(-) 2

years ago when he stopped PrEP (“wasn’t having that much sex”)

• History of depression, not currently being treated
• Hypertension, controlled on Lisinopril
• HIV RNA 120,000 c/mL; CD4 count 375 cells/mm3; HLAB*5701(-),

genotype = wild-type

• eGFR>60
• TC 180 HDL 34 LDL 120 TG 200
• 1. dolutegravir/abacavir/3TC

(1 tab daily)

• 2. bictegravir/FTC/TAF

(1 tab daily)

• 3. doravirine/3TC/TDF

(1 tab daily)

• 4. DRV/c/FTC/TAF

(1 tab daily)

• 5. dolutegravir + 3TC

(2 tabs daily)

• 6. dolutegravir/rilpivirine

(1 tab daily)

Case 6: panelists, new drugs/strategies for initial therapy in 2018 Question: How do you balance ce virologic c efficacy cy and cardiovascu cular, renal comorbidities in tr treatm tment s t simpl plificati tion? n?

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Case 7:

• 58, HIV(+) since 1990s
• peak HIV RNA >100,000 c/mL; nadir CD4 <50 cells/mm3
• History of exposure to nevirapine, d4T, 3TC, nelfinavir, with periods of meth

use, intermittent viremia, culminating in virologic failure with (list of mutations):

• Suppressed in 2006 with unboosted ATV (due to hyperlipidemia, recurrent

pancreatitis), TDF, 3TC, T-20. virus is mixed CCR5/CXCR4 tropic.

• TDF switched to ABC due to CKD in 2008; CrCl currently 51.
• Lipids are TC167 H28 L??? TG783 on atorvastatin and fenofibric acid
• CV risk score:
• Currently suppressed on ATV 400 BID, RAL 400 BID, ABC/3TC

Case 7: (how) would you modify his regimen

• 1. ATV BID + RAL BID + ABC 600 mg/3TC 300mg QD (no change)
• 2. DRV/r + DTG + 3TC
• 3. DRV/r + DTG + FTC/TAF
• 4. DTG + RPV
• 5. DTG + DRV/r
• 6. ATV/r + 3TC
• 7. EVG/cobi/FTC/TAF + DRV

Thanks!

D:A:D: Exposure to ATV/RTV or DRV/RTV and Risk of CVD

§ Prospective analysis of pts followed from 2009 to earliest CVD, last visit + 6 mos, or 2/1/2016 (N = 35,711)

– 1157 pts (3.2%) developed CVD (MI, stroke, sudden cardiac death, invasive CV procedure)

§ Cumulative exposure to DRV/RTV, but not ATV/RTV, associated with increased CVD risk in multivariate analysis: 59% risk increase per 5 yrs of DRV/RTV

– Association does not appear to be mediated through dyslipidemia, in contrast with first-generation PIs

Ryom L, et al. CROI 2017. Abstract 128LB. Relationship Between 5-Yr Exposure to ARVs and CVD ATV/RTV DRV/RTV

CVD Risk per 5 Yrs of ARV Exposure, IRR (95% CI) Model ATV/RTV DRV/RTV Univariate 1.25 (1.10-1.43) 1.93 (1.63-2.28) Multivariate § Baseline adjusted* 1.03 (0.90-1.18) 1.59 (1.33-1.91) § Time-updated adjusted* 1.01 (0.88-1.16) 1.53 (1.28-1.84)

*Adjusted for: BMI, CKD, DM, CD4, dyslipidemia. 2.5 2.0 1.5 1.0 0.5 CVD Incidence Rate Ratio (95% CI) No exposure Univariate MV: BL adj model MV: Time-updated adj model Slide credit: clinicaloptions.com

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D:A:D: Cumulative Exposure to ARVs Associated With Increased CKD Risk

CKD Risk by Yrs of ARV Exposure, Incidence Rate Ratio* (95% CI) Drug 1 Yr 5 Yrs TDF 1.14 (1.10-1.19) 1.94 (1.57-2.39) ATV + RTV 1.20 (1.13-1.26) 2.44 (1.86-3.21) LPV/ RTV 1.11 (1.06-1.16) 1.66 (1.32-2.09)

Mocroft A, et al. Lancet HIV. 2016;3:e23-e32.

*Multivariate analysis. For each value, P < .0001

Slide credit: clinicaloptions.com

1.2 1.1 1.0 0.9 0.8 ATV + RTV LPV/RTV TDF Incidence Rate Ratio (95% CI) Univariate Multivariate 1.5 1.4 1.3

P value (univariate) P value (multivariate) < .0001 < .0001 < .0001 < .0001 < .0001 < .0001

550 Clinic: Real-World Virologic Suppression by Regimen in Pts With M184V Mutation

§ Retrospective cohort study using medical records of new pts presenting to University of Louisville outpatient HIV clinic from January 2003 to July 2016

– Analysis of tx-naive (2%) or tx-experienced (98%) pts with M184V mutation: N = 100 pts, 167 regimens Regimens With < 3 Fully Active Drugs

Kirkpatrick L, et al. IDWeek 2017. Abstract 1372. Slide credit: clinicaloptions.com *Predefined noninferiority criteria not met for regimens with < 3 vs ≥ full active drugs.

72 69 100 80 20 HIV-1 RNA < 200 c/mL (%) < 3 ≥ 3 60 40

n/N = 11/ 16 108/ 151

P = .11* Fully Active Drugs 69 84 85 21 78 100 80 20 HIV-1 RNA < 200 c/mL (%) PI INSTI 60 40

n/N =

80

21/ 25 59/ 86 56/ 72 17/ 20 4/ 5 3/ 14

Overall HIV-1 RNA < 100,000 c/mL HIV-1 RNA ≥ 100,000 c/mL 71 100 100

10/ 14 7/ 7 4/ 4

PI INSTI PI INSTI EVG RAL DTG P = .13 P = .51 P = .04

§ Randomized, open-label phase III trial in which pts in sub-Saharan Africa with virologic failure on NNRTI + 2 NRTIs treated with LPV/RTV + RAL, LPV/RTV + 2-3 NRTIs, or LPV/RTV monotherapy* (N = 1277)

100 80 60 40 20 Pts (%)

EARNEST: Boosted PI + NRTIs Noninferior to Boosted PI + RAL

Paton NI, et al. N Engl J Med. 2014;371:234-247. Paton, NI, et al. ACHA 2015. LPV/RTV + 2/3 NRTIs (n = 426) LPV/RTV + RAL (n = 433) LPV/RTV monotherapy (n = 418) 100 80 60 40 20 Pts (%)

HIV-1 RNA < 50 copies/mL, Wk 96[1] 73 74 44 P < .001 HIV-1 RNA < 400 copies/mL, Wk 144[2]

LPV/RTV + NRTI (Number of Active NRTIs) 88 LPV/ RTV + RAL 77 81 85 61 1 2-3 LPV/ RTV *Pts had no prior PIs; pts receiving monotherapy received 12 wks of LPV/RTV + RAL. Slide credit: clinicaloptions.com

Study 119: Switch to EVG/COBI/FTC/TAF + DRV in Treatment-Experienced Pts

§ Multicenter, open-label, randomized phase III trial

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24 – 39% pts receiving ≥ 6 pills/day at baseline

Huhn GD, et al. IDWeek 2015. Abstract 726. Huhn GD, et al. J Acquir Immune Defic Syndr. 2017;74:193-200.

Treatment-experienced pts, HIV-1 RNA < 50 c/mL for ≥ 4 mos on DRV- containing ART, with history of drug resistance* and eGFR ≥ 50 mL/min (N = 135) Switch to EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 89) Wk 144 Wk 48 Baseline ART (n = 46) EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 46) Wk 24

*Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and/or K65R, but not integrase inhibitors (unless currently receiving RAL, EVG, or once-daily DTG), and no DRV resistance. Slide credit: clinicaloptions.com

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Study 119: Virologic Suppression After Switch to EVG/COBI/FTC/TAF + DRV

Slide credit: clinicaloptions.com Huhn GD, et al. J Acquir Immune Defic Syndr. 2017;74:193-200.

Virologic Failure HIV-1 RNA < 50 c/mL No Data 100 80 60 40 20 Pts (%) 97 91 2 1 9 HIV-1 RNA < 50 c/mL Virologic Failure No Data 94 76 2 11 3 13 Treatment difference: 5.3% (95% CI: -3.4% to 17.4%; P = .23) Treatment difference: 18.3% (95% CI: 3.5% to 33.0%; P = .004) Wk 24 Virologic Efficacy Wk 48 Virologic Efficacy 100 80 60 40 20 Pts (%) EVG/COBI/FTC/TAF + DRV Baseline ART EVG/COBI/FTC/TAF + DRV Baseline ART

Summary Points