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 Hauke Walter Dr. Joachim Büch Dr. Stefan Scholten In den RingColonnaden
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)
Geno2pheno Sequence sampling date 17.02.2004 P10 PROTEASE K20KQ, M36IM, S37A, P39S, R57K, L63A, A71V, V77I, I93L P51 REVERSE TRANSCRIPTASE V60IV, K64HN, D67DN, T69NT, K70R, E122K, D123E, I135LV, I142V, K166R, D177DE, I178IM, M184V, Q197K, R211K, L214F, K219Q 7
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):
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 9
Interpretation view provides an explanation for therapy rating Interaction of resistance mutations and drugs result in further positive weights Weights for basis effectiveness of drugs
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 in ETR EAP: KVX + LPV/r + SQV + ETR + T20 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)
2018 LTFU from 03/17 to 02/18 BUT he had taken about ONE (blistered) DOSE (morning or evening) once in a while – (estimated every third day) HIV RNA (23.02.) <40 cps/ml (!) Unable to maintain the amount of pills any more - options?
RESISTANCE TESTS 2007 / 2012 PRESENT ART: 3TC/ABC+ETR+LPV/R+SQV+DTG+MVC 2007 2012 2007 2012 ≠F53L ≠F53L ≠F53L NRTI PI ≠F53L ≠F53L ≠F53L ≠F53L 2012 2007 2007 2012 +L100I NNRTI +L100I +L100I +L74M, T97A +L100I INI INI naiv +L74M, T97A 2007 2012 +L74M, T97A, Y134R FI +V38A FI - naiv CCR5 FPR 7,4% (fraglich R5-trop) L45M
WHAT are our options now ??? 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: 17 X + TPV/r ?????????????? (twice daily, diarrhea, pillburden, side effects)
? ?
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 HIV VL 7868/ml; CD4: 186/µl (14,3%) Truvada Intelence Prezista/r (b.i.d.) Isentress Tropismus: X4-trop (1,7% FPR)
Therapieverlauf 44088 HIV RNA HCV RNA CD4 10.000.000 2.000 1.800 1.000.000 1.600 HIV RNA [Kopien/ml] 100.000 1.400 12 weeks IFN+RBV 1.200 10.000 stop due to non response 1.000 & major depression 1.000 CD4 [Zellen/µl] 800 67 600 100 64 21,8% <40 (n.d.) 400 10 200 9,8% 1 0 0 0 1 1 2 2 2 2 3 3 4 5 5 6 6 0 1 1 1 2 2 3 3 4 4 5 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 g l z n g l l l g t z b i p z b p v z b i v b t b v u u u u k a a k e e r o e o o u e e u e u e e u e e O J M J O J J M M D D N D N N A F F J F A F F A S S TDF FTC ETR DRV/r (bid) RAL
RESISTANCE TEST 2015 (PROVIRAL DNA) 11/2015 FTC TDF ETR DRV DTG RAL Tropismus (08/10): X4-trop (1,7% FPR) = ART Auswahl
LTFU from 03/2017 until 02/2018 !!! Therapieverlauf 44088 HIV RNA HCV RNA CD4 10.000.000 2.000 1.800 1.000.000 313.000 cps/ml 1.600 HIV RNA [Kopien/ml] 119/µl (10,1%) 100.000 1.400 1.200 10.000 1.000 12 weeks IFN+RBV 1.000 CD4 [Zellen/µl] stop due to non response 800 & major depression 22,5% 600 100 67 64 400 <40 (n.d.) 10 200 1 0 9,8% 0 0 1 1 2 2 2 2 3 3 4 5 5 6 6 7 0 1 1 1 2 2 3 3 4 4 5 8 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 g l z n g l l l g z t z b i p z b p v z b i v b t b v u u u u k a a k e e r o e o o r 2 u u u u e e e e e e e O J M J O J J M M M D D N D N N . A F F J F A F F A S S 2 0 . 3 2 TDF TAF TDF FTC FTC ETR DRV/r (bid) DRV/c RAL DTG
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 32
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GENO2PHENO NEW AREVIR2019 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 35
SYMTUZA
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