HIV RESISTENCE/ HIV TROPISM AREV I R 2 0 1 9 S TA D T H OT E L A - - PowerPoint PPT Presentation

HIV RESISTENCE/ HIV TROPISM

AREV I R 2 0 1 9

S TA D T H OT E L A M RÖ M E RT U R M , K Ö L N 0 3 . – 0 4 . M A I 2 0 1 9 In den RingColonnaden

• Dr. Stefan Scholten
• Dr. Joachim Büch

Hauke Walter

F I NANCI AL DI SCL OSURE

Abbott/abbvie, BMS, Gilead, GSK, Hexal, Hormonsan, Janssen-Cilag, MSD, TAD, ViiV Healthcare

1 new case and 2 updates from 2018:

• I hoped never to see this again …
• One of those patients … (an update again)
• It‘s never as easy as one thinks! (update)

1 new case and 2 updates from 2018:

• I hoped never to see this again …
• One of those patients … (an update again)
• It‘s never as easy as one thinks! (update)

MSM, German, 45 years of age, HIV diagnosis 1995, CDC stage B2 (Herpes Zoster) First „HIV Therapy“ 1995:

• St. John‘s Wort

After 6 „herbal“ years he went to see another doctor… 2001 ART: d4T + 3TC (possibly +X?)

MSM, German, 45 years of age, HIV diagnosis 1995, CDC stage B2 (Herpes Zoster) First „HIV Therapy“ 1995:

• St. John‘s Wort

After 6 „herbal“ years he went to see another doctor… 2001 ART: d4T + 3TC (possibly +X?) 2004 ART: AZT/3TC + LPV/r

(initially reduced dose, after al „blip“ full dose)

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Geno2pheno Sequence sampling date 17.02.2004 P10 PROTEASE P51 REVERSE TRANSCRIPTASE

K20KQ, M36IM, S37A, P39S, R57K, L63A, A71V, V77I, I93L V60IV, K64HN, D67DN, T69NT, K70R, E122K, D123E, I135LV, I142V, K166R, D177DE, I178IM, M184V, Q197K, R211K, L214F, K219Q

MSM, German, 45 years of age, 2017 he came to see me for a second opinion:

• worried about the risk of lipodistrophy
• frequent, sometimes massive diarrhea
• viral load was since 2005 undetectable

… so we performed yet another resistance test (proviral):

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Geno 2 pheno Sequence sampling date 28.03.2017 P10 PROTEASE V3I, S37A, R57K, L63AT, A71V, V77I, I93L P51 REVERSE TRANSCRIPTASE K70KR, K101KQ, E122K, D123E, I135IV, I142V, K166R, D177DE, I178IL, M184MV, Q197K, R211K, L214F, V245M, P272A, K275R, R277G

Interaction of resistance mutations and drugs result in further positive weights Weights for basis effectiveness of drugs

Interpretation view provides an explanation for therapy rating

MSM, German, 45 years of age,

04/2017 DTG + RPV No more diarrhea, no relevant side effects, viral load remains undetectable 08/2018 DTG/RPV (simplification) Still undetectable, patient very happy - he DID find DoRi …

1 new case and 2 updates from 2018:

• I hoped never to see this again …
• One of those patients … (an update again)
• It‘s never as easy as one thinks! (update)

45 years, male, MSM Ethnicity: caucasian (spanish) Date of HIV infection: unknown Date of HIV Diagnosis: 1991 CDC-Classification: C 3 Multiple and all failing ARTs since 1993

GT resistance test 07/2007 Tropism (Trophile): Dual/Mixed INI: Y143R FI: n.d. NRTI: M41L E44D D67N T69D V75M V118I M184V L210W T215Y NNRTI: K101E G190S PI: L10I V32I L33F M46I I47V F53L I54M Q58E N83D L90M

ART commenced 01.08.2012 in DTG CUP:

KVX + LPV/r + SQV + ETR + MRV + DTG (2x50mg) Since then he contracted his first syphillis, 3 months later an acute Hepatitis C (GT1a) Then it became clear that he was frequently slamming Crystal Meth He developed a major depression and borderline personality disorder (ongoing)

ART in ETR EAP: KVX + LPV/r + SQV + ETR + T20

2018

LTFU from 03/17 to 02/18 BUT he had taken about ONE (blistered) DOSE

(morning or evening)

• nce in a while – (estimated every third day)

HIV RNA (23.02.) <40 cps/ml (!)

Unable to maintain the amount of pills any more

• options?

+V38A L45M

RESISTANCE TESTS 2007 / 2012 PRESENT ART: 3TC/ABC+ETR+LPV/R+SQV+DTG+MVC

+L100I +L100I +L100I +L100I

2012 2007 2012 2007 2012 2007

≠F53L ≠F53L ≠F53L ≠F53L ≠F53L ≠F53L ≠F53L

2012 2007

+L74M, T97A, Y134R +L74M, T97A +L74M, T97A

INI naiv FI - naiv 2012 2007 NRTI NNRTI FI PI INI CCR5

FPR 7,4% (fraglich R5-trop)

Option 1: Leave everything as it is … (he is taking only half his ART every third day !!!!) Option 2: D/C/F/TAF + DTG/RPV + MRV 300 qd ????? Option 3: DTG + MK1439(Doravirine)+ MRV +/- Ibalizumab (Trogarzo) iv. every 2 weeks ???

(Trogarzo = 118.000,- $ / year)

Option 4: X + fosTemsavir ??? (is to be given TWICE DAILY!!!) ??? Option 5: X + TPV/r ?????????????? (twice daily, diarrhea, pillburden, side effects)

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WHAT are our options now ???

? ?

New Geno2Pheno prediction !!!

P31 INTEGRASE

D10E, E11D, R20K, V31I, V72I, L74M, T97A, S119G, T122I, G123S, A124T, T125A, R127K, Y143R, V201I, K215N, N232D, L234V, D279G

P51 REVERSE TRANSCRIPTASE

M41L, K43Q, E44D, V60I, D67N, T69D, V75M, L100I, K101E, V118I, D123NS, I142V, K166R, I178M, V179LV, M184V, G190S, G196E, E203K, Q207E, H208F, L210W, R211K, L214F, T215Y, K219EK

P31 INTEGRASE

D10E, E11D, R20K, V31I, V72I, L74M, T97A, S119G, T122I, G123S, A124T, T125A, R127K, Y143R, V201I, K215N, N232D, L234V, D279G

ART as from 20th July 2018:

D/c/F/TAF + DTG/RPV + MRV 300

1 new case and 2 updates from 2018:

• I hoped never to see this again …
• One of those patients … (an update again)
• It‘s never as easy as one thinks! (update)

MSM, German, 62 years of age, Retired federal law enforcement officer, diplomatic corps HIV diagnosis 1996 CDC stage C3 First ART 1997

ART HISTORY

First ART: 03/97 d4T, ddI, NFV 09/2001 University Hospital Bonn HIV PCR: >100.000 cps/ml CD4: <200µl Diag: Cryptosporidiosis, Syphilis Resistance test: multiple NUC and PI Mutations New ART 10/2001: ABC, 3TC, TDF, EFV, LPV/r Soon after that -> LTFU due to transfer abroad Reappeared in my practice in Cologne 2010

RESISTANCE TEST 2010

Tropismus: X4-trop (1,7% FPR) Truvada Intelence Prezista/r (b.i.d.) Isentress

HIV VL 7868/ml; CD4: 186/µl (14,3%)

1 10 100 1.000 10.000 100.000 1.000.000 10.000.000

A u g 1 O k t 1 D e z 1 F e b 1 1 M a i 1 1 J u l 1 1 S e p 1 1 D e z 1 1 F e b 1 2 M r z 1 2 J u n 1 2 S e p 1 2 N

• v

1 2 D e z 1 2 F e b 1 3 M a i 1 3 A u g 1 3 N

• v

1 3 F e b 1 4 J u l 1 4 O k t 1 4 F e b 1 5 J u l 1 5 N

• v

1 5 J u l 1 6 A u g 1 6

HIV RNA [Kopien/ml] 200 400 600 800 1.000 1.200 1.400 1.600 1.800 2.000 CD4 [Zellen/µl]

67 9,8% <40 (n.d.)

Therapieverlauf 44088

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HIV RNA HCV RNA CD4 TDF FTC ETR DRV/r (bid) RAL 12 weeks IFN+RBV stop due to non response & major depression

21,8%

RESISTANCE TEST 2015

(PROVIRAL DNA) 11/2015

Tropismus (08/10): X4-trop (1,7% FPR)

FTC

= ART Auswahl

DTG TDF ETR DRV RAL

1 10 100 1.000 10.000 100.000 1.000.000 10.000.000

A u g 1 O k t 1 D e z 1 F e b 1 1 M a i 1 1 J u l 1 1 S e p 1 1 D e z 1 1 F e b 1 2 M r z 1 2 J u n 1 2 S e p 1 2 N

• v

1 2 D e z 1 2 F e b 1 3 M a i 1 3 A u g 1 3 N

• v

1 3 F e b 1 4 J u l 1 4 O k t 1 4 F e b 1 5 J u l 1 5 N

• v

1 5 J u l 1 6 A u g 1 6 M r z 1 7 2 3 . 2 . 2 1 8

HIV RNA [Kopien/ml] 200 400 600 800 1.000 1.200 1.400 1.600 1.800 2.000 CD4 [Zellen/µl]

67 9,8% <40 (n.d.) 22,5%

Therapieverlauf 44088

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HIV RNA HCV RNA CD4 TDF FTC ETR DRV/r (bid) RAL 12 weeks IFN+RBV stop due to non response & major depression DTG DRV/c TDF FTC TAF

LTFU from 03/2017 until 02/2018 !!!

313.000 cps/ml 119/µl (10,1%)

RESISTENCE TEST 201816.02.18

ULTRA DEEP SEQ 16.02.18

NEW ART … … AND FUTURE OPTION

13.03.2018 restarted ART: D/C/F/TAF 1 – 0 – 0 DTG 1 – 0 – 1 DRV 600 0 – 0 – 1 Cobi 150 0 – 0 – 1

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33

34

GENO2PHENO NEW AREVIR2019

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P10 PROTEASE

V3I, L10IL, I13V, K20KM, S37N, I62IV, L63LP, I64V, V77IV, I84IV, L90LM

P51 REVERSE TRANSCRIPTASE

V35ILV, M41LM, A62AV, S68NS, K70EGKR, V75IMV, F77FL, K101EK, K103KN, E122EK, I135IV, E138A, I142IT, Q151KLMQ, I202IV, L214F, K238KR, D250E, P272A, R277K, I293V

P31 INTEGRASE

A38AG, K46KT, V72I, L101IL, T112IT, I113IL, G123S, A124T, R127K, N232D

SYMTUZA

3 7

EMERALD: Phase I I I , Random ized, Open-label, Multicenter Trial

* Stratified by bPI (protease inhibitor boosted with low-dose ritonavir or COBI) at screening; †DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V (IAS-USA)

Key inclusion criteria:

• On a stable bPI + F/ TDF regimen for at least 6 months
• Viral load (VL) <50 c/mL for ≥2 months before screening; one 50≤VL<200 c/mL within 12 months prior to screening allowed
• Creatinine clearance (by Cockcroft-Gault) ≥50 mL/min
• Previous ART virologic failure (VF) allowed
• Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs†

Baseline W eek 9 6

Random ization*

2 :1

N= 1 1 4 9

W eek 4 8

Primary endpoint

Screening phase Treatm ent phase

D/ C/ F/ TAF

Extension phase ≤30 days prior to baseline

W eek 2 4

Interim analysis

D/ C/ F/ TAF

Continue bPI + F/ TDF

D/C/F/TAF

Roll-over phase

Objective: Assess efficacy (non-inferiority) and safety of switching to D/ C/ F/ TAF vs continuing bPI + F/ TDF regimens in virologically suppressed HIV-1-infected adults at Week 48

Lancet HIV. Orcin, C, et.al. 2018 Jan;5(1):e23-e34

D/ C/ F/ TAF Sw itch by Prior ARV: Baseline Dem ographics

3 8 * Percentages may not total 100% due to rounding. †Includes ARVs used at screening and boosting agents. One (< 1% ) patient was included in the study despite having only 3 prior ARVs used due to a data recording error; this patient was in the control arm and was excluded from the subgroup analyses.D/ C/ F/ TAF, darunavir/ cobicistat/ emtricitabine/ tenofovir alafenamide; ARV, antiretroviral.

Parameter D/C/F/TAF (N=763) Control (N=378) Demographic Characteristics Age, median (range), y 46 (19-75) 45 (20-78) Female, n (%) 140 (18) 65 (17) Race, n (%) White 573 (75) 282 (75) Black or African American 155 (20) 82 (22) Other 35 (5) 14 (4) Clinical Characteristics CD4+ cell count, median (range), cells/μL 630 (111-1,921) 624 (131-1,764) Prior VF, n (%) 647 (85) 325 (86) ≥1 116 (15) 53 (14) Number of prior ARVs used, n (%)*,† 4‡ 316 (41) 160 (42) 5 98 (13) 56 (15) 6 69 (9) 30 (8) 7 69 (9) 30 (8) >7 211 (28) 101 (27) Lancet HIV. Orcin, C, et.al. 2018 Jan;5(1):e23-e34

3 9

• No discontinuations for efficacy reasons
• Most rebounders (12/ 19 D/ C/ F/ TAF and 4/ 8 control) resuppressed (< 50 c/ mL) at Week 48

WEEK 48 EFFICACY

2.5% (n=1 9) 2.1% (n=8 )

20 40 60 80 100

D/C/F/TAF (N=763) Control (N=378)

Proportion of patients (% )

% confirmed virologic rebound cumulative through W eek 4 8

∆0.4% (95% CI: – 1 .5 ; 2 .2 * )

[WERT]% [WERT]%

(n=6)

[WERT]%

(n=33)

[WERT]% [WERT]%

(n=2)

[WERT]%

(n=22)

20 40 60 80 100

Virologic… VL ≥50 c/mL† No virologic data

Proportion of patients (%)

∆ 1.2% (95% CI −1.7; 4.1)

FDA-Snapshot analysis at W eek 4 8

†Last VL in W48 window ≥50 c/mL, or discontinuation for efficacy reasons, or

premature discontinuations (≠efficacy/AE/death), with last (single) VL≥50 c/mL ( n= 7 2 4 ) ( n= 3 5 4 )

* Upper bound 95% CI < 4.0% (p< 0.0001)

Lancet HIV. Orcin, C, et.al. 2018 Jan;5(1):e23-e34

AND AGAIN: inadherence and no show for 6 month (money and family problems, beeing massively ashamed)

ART as from 07th Januar 2019:

D/c/F/TAF + DTG 50

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AGAIN: inadherence and no show for 6 month (money and family problems, beeing massively ashamed)

ART as from 07th Januar 2019:

D/c/F/TAF + DTG 50 For the sake of discuccion and in view of the Emerald data: Is THIS worth trying?

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man vs. machine to make this work, we need your cooperation and input!

„Die Versuchung des heiligen Antonius“ von Ralph König

Vielen Dank!