A case, and some pharmacological considerations. from the perspective of a virologist. Anna Maria Geretti University of Liverpool, United Kingdom

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1 A case, and some pharmacological considerations. from the perspective of a virologist Anna Maria Geretti University of Liverpool, United Kingdom 1

2 Case History: Mr RS 53-year-old male Diagnosed HIV positive in 1999 Baseline CD4 count 46 cells Baseline viral load 83,000 cps Subtype C Past hepatitis B infection Hepatitis C negative Oct 1999 starts AZT/3TC + IDV

3 Medical and ART history Date started Date stopped ART Viral load CD4 Resistance Oct 1999 Oct 2000 AZT/3TC IDV Oct 2000 Nov 2001 ABC/3TC EFV 31, Nov 2001 Jul 2004 TDF d4t 3TC LPV/r < Jul 2004 Jul 2008 TDF ATV FPV/r Jul 2008 Nov 2011 TDF RAL DRV/r (600/100 bid) <50 to RT: 67N 215Y 184V 74V 100I 103N RT: None PR: 32I

4 Mr RS Which is your preferred strategy? 1. Do nothing as long as the viral load is <200 cps 2. Address patient-related psyco-social issues & adherence 3. Address sample- and/or lab-related technical issues 4. Request more tests which? 5. Change or intensify the ART regimen

5 Management strategies Review: Technical issues of viral load testing Adherence, tolerability, psycho-social issues Expected potency of the regimen Drug-drug interactions (DDIs) and food requirements Reasonable to perform a drug resistance test Reasonable to check drug levels CD4 nadir and pre-art viral load inform Size of HIV DNA reservoir Likelihood of compartmentalised virus replication

6 Plasma HIV-1 RNA during ART Spivak et al. Trends Mol Med 2016

7 HIV-1 DNA log 10 cps per 10 6 CD4 T-cells Cellular HIV-1 DNA load during suppressive ART Cohort started 2 NRTIs + EFV or NVP, achieved VL <50 cps within 6 months, and during subsequent follow-up had VL consistently <50 cps (no blips or interruptions) while remaining on the initial NNRTI (n=104) Years of suppressive ART Mean change integrated HIV-1 DNA for 10 yrs of ART (log 10 cps/10 6 PBMC) +0.2 [95% CI -0.2, +0.6; p 0.28] Geretti et al. Int. Workshop HIV & Hepatitis Viruses Drug Resistance 2013; Ruggiero et al. EBioMed 2015

8 Virus replication in sanctuary compartments due to poor drug penetration or activity Virus reactivation in latently infected cells, with presence of ART ensuring that new cells cannot be productively infected

9 Untimed drug levels & resistance test at LLV predict viral load rebound >1000 cps First LLV plasma sample: PI/NNRTI concentration and resistance test (n=328) Concentrations classed as therapeutic' or suboptimal' based on target C trough Genotypic sensitivity score (GSS) of regimen by Stanford algorithm Independent predictors of VL rebound >1000 cps (adjor) o Suboptimal drug levels = 2.53 (95% CI ; p<0.001) o GSS <3 = 1.55 (95% CI ; p=0.04) o LLV (cps): = 2.48 (95% CI ) = 2.36 (95% CI ) = 3.65 (95% CI )(p<0.001) Gonzalez-Serna et al. CROI 2015

10 Low drug levels predict faster resistance Gonzalez-Serna et al. CROI 2015

11 Case History: Mr RS DRV plasma concentration in range Plasma resistance test (RT, PR, IN) wild-type X 3 CSF HIV RNA 3128 cps/ml CSF resistance test RT: 67N 215Y 184V 100I 103N PR: wild-type IN: RT 155H

12 HIV-1 RNA Detection in CSF according to LLV HIV-1 RNA measured in paired plasma and CSF of 43 subjects with plasma VL <50 cps over 12 months of ART and in 40 subjects with a history of LLV HIV-1 RNA detected in CSF in 0/43 vs. 9/40 (22%) respectively Detection of HIV-1 RNA in CSF associated with low nadir CD4 count (p=0.030) and black heterosexual exposure group (p=0.007) but not with drug concentration or CPE score Nightingale et al. J NeuroVirol 2016

13 HIV-1 RNA cps/ml SAILING Case-1 ART-experienced, INI-naïve TDF FTC + DTG 50 mg OD PDVF Wk cps/ml Confirm Wk cps/ml 386 cps/ml INI mutation PDVF= Protocol-defined virological failure; FC = Fold change; RC = Replication capacity Day 1 PDVF Confirm. HIV-1 RNA A49G, S230R, R263K A49G, S230R, R263K DTG FC RAL FC INI RC 20% 7.1% 12% No NRTI resistance at any time point Underwood et al. European HIV & Hepatitis Workshop 2015

14 HIV-1 RNA cps/ml SAILING Case-2 ART-experienced, INI-naïve ABC 3TC + DTG 50 mg OD PDVF Wk cps/ml Confirm Wk 108 retest 407 cps/ml 1000 Day 1 PDVF Week HIV-1 RNA IN mutation - N155H DTG FC RAL FC IN RC NR b NR PDVF BR: No emergent resistance, loss of M184M/V PDVF= Protocol-defined virological failure; FC = Fold change; RC = Replication capacity Underwood et al. European HIV & Hepatitis Workshop 2015

15 You plan to modify the ART regimen Which is your preferred strategy? 1. DRV/b + DTG 2. DRV/b + DTG + ETR 3. DRV/b + DTG + MVC 4. DRV/b + MVC + ETR 5. DRV/b + DTG + MVC + ETR Add TDF or TAF to any of the above, +/- FTC? Which dose of DTG?

16 Pharmacology of integrase inhibitors Dose DTG EVG RAL 50mg od (50-100mg bd) 150mg od (boosted) 400mg bd Potent inhibitors of integrase enzyme Protein binding-adjusted IC90/95 values in the low ng/ml range - High inhibitory quotient (IQ) - DTG > EVG > RAL Each INI has unique PK/PD properties PK variability highest for RAL and lowest for DTG

17 Pharmacology of integrase inhibitors Different hepatic metabolism: RAL and DTG minimal cytochrome P450 (CYP) involvement; EVG primarily thorugh CYP3A4 RAL and DTG have minimal DDI profiles EVG requires boosting to be amenable to OD dosing and has greater DDI potential manageable as with RTV Podany et al. 2016

18 Pharmacology of integrase inhibitors Dose DTG EVG RAL 50mg od (bd if INI experienced) 150mg od (boosted) 400mg bd Food effect on drug exposure Take with food if possibility of INI resistance Take with food Take without regard to food Low ( 33%), moderate ( 41%), and high ( 33%) fat meals increased AUC Light ( 36%), and high ( 91%) fat meals increased AUC High fat doubles AUC, food increases variability Absorption affected by divalent / trivalent cations, such as those found in multivitamins and antacids

19 DTG mean plasma concentration (ng/ml) Effect of food on DTG exposure - healthy volunteers Fasting Low fat Moderate fat High fat 500 PA-IC µg/ml *50 mg formulation Time (hours) Low, moderate, and high fat meals increase DTG AUC by 33%, 41%, and 66%, respectively. In INI-naive patients, dose with or without food. In INI-resistant patients, dose with food. Song et al. Antimicrob Agents Chemother 2012

20 INI chelation with cations Mean DTG concentration (µg/ml) Al/Mg containing antacid taken together Antacid +/- 2h after EVG 74% 26% Dolutegravir alone Dolutegravir +antacid Dolutegravir + antacid 2h later Time (hrs) EVG AUC Decreased 45% EVG C min Decreased 41% Binding of integrase inhibitors Mg 2+ Mg 2+ Patel et al. JAC 2011; Pommier et al. Nat Rev 2005; Stribild SmPC June 23rd 2015; Tivicay SmPc Oct 1st 2015 Mg Mg Not recommended RAL Separate DTG and EVG/c

21 Impact of acid-reducing agents and multivitamins on DTG exposure Co-administered drug DTG C or C 24 Geometric mean change Recommendation Antacids and supplements Magnesium / aluminiumcontaining antacid AUC* 74% Calcium supplements 39% Iron supplements 56% Multivitamins 32% Acid-lowering agents Take antacids and supplements a minimum of 2 hours after or 6 hours before DTG 1 Omeprazole 5% No significant effect observed 2 C : Trough concentration 1. Tivicay SmPC January Patel et al. J Antimicrob Chemother 2011

22 Pharmacology of integrase inhibitors Dose DTG EVG RAL 50mg od (bd if INI experienced) 150mg od (boosted) 400mg bd Food effect Take with food if possibility of INI resistance Low ( 33%), moderate ( 41%), and high ( 33%) fat meals increased AUC Take with food Light ( 36%), and high ( 91%) fat meals increased AUC Take without regard to food High fat doubles AUC, food increases variability Metabolism UGT1A1 (CYP3A 10-15%) CYP3A / UGT1A1/3 UGT1A1 Protein binding >99% 99% 76-83% Half life 11-12h 9h 9h Dose-exposure Dose proportional Less than Nearly up to 100mg dose-proportional dose-proportional

23 DTG distribution and CSF penetration Plasma protein binding: >99% 1 Blood:plasma ratio: minimal association with blood cellular components 1 A Phase IIIb study assessed the distribution of DTG in CSF 2 DTG concentrations observed in CSF at both Week 2 and Week 16 averaged 18 ng/ml (comparable to unbound concentration) and exceeded the in vitro IC 50 against wildtype viruses (0.2 ng/ml) 2 for all subjects, suggesting that DTG was able to achieve therapeutic concentrations in the CSF 1. Tivicay SmPC, January 2014; 2. Letendre et al. CROI 2013

24 Special groups Swallowing DTG EVG RAL Granule being developed ( bioavailability) Cannot be chewed or crushed Chewable tablets, granules ( bioavailability) Children Not licensed <12y Not licensed <18y, avoid <6y Pregnancy No data FDA Cat B Limited data FDA Cat B Licensed from 4 weeks Some data FDA Cat C Renal impairment No adjustment DTG exposure reduced in severe renal disease FDC with TDF not <70, stop <50 FDC with TAF >30 No adjustment Cirrhosis CP-A No adjustment No adjustment No adjustment CP C Caution Not recommended Caution

25 Mean DTG concentration (µg/ml) Dose-exposure relationship for DTG DTG PK parameters at Week 2 by dose in the SPRING-1 Phase IIb trial 1, mg QD 2 25 mg QD 2 50 mg QD 2 QD dose C max (μg/ml) AUC 0 (µg h/ml) C (µg/ml) IQ mg 1, (37) 16.0 (40) 0.30 (71) PA-IC µg/ml* 25 mg 1, (43) 23.1 (48) 0.54 (67) mg 1, (27) 48.1 (40) 1.20 (62) 19 Values shown are geometric means (CV%) Post-dose time (hours) DTG shows low to moderate PK variability 1,2 All drug levels well above the in-vitro PA-IC 90 of μg/ml 1,2 *PA-IC 90 is the protein-adjusted 90% inhibitory concentration Inhibitory quotient is defined as C /PA IC van Lunzen et al. Lancet Infect Dis 2012; 2. Rockstroh et al. HIV

26 Responders, % SAILING: Response rates by quartile of DTG c 0_avg SAILING: Phase III study in ART-experienced, INI-naïve subjects 100 Responders Non-responders μg/ml ( ) Response rate 63.5% μg/ml ( ) Response rate 72.9% C 0_avg quartile μg/ml ( ) Response rate 82.4% μg/ml ( ) Response rate 75.3% The average plasma concentration of DTG was a significant predictor of virological response: subjects in the lowest quartile had a lower response Song et al. ICAAC 2013

27 DDI liability DTG EVG RAL Metabolism UGT1A1 (CYP3A 10-15%) CYP3A UGT1A1/3 UGT1A1 Perpetrator of DDIs No effect on CYPs, UGTs. Inhibits OCT2 Cobicistat potent CYP3A, mod CYP2D6 and MATE1 EVG mod inducer of CYP2C9 No effect on CYPs, UGT or PgP Divalent cations Al/Mg/Ca/Fe/Multivit amins Separate -6 or +2h Al/Mg antacids ±2h Multivitamins ±4h Al/ Mg contraindicated Ca: not clinically meaningful Gastric ph No significant interaction No significant interaction RAL absorption with OMP ( 39%) / FAM ( 45%); no adjustment needed

28 DTG interactions Oral contraceptives 1 Commonly used medications H 2 -receptor antagonists (e.g.,ranitidine, cimetidine) 2 Prednisone 1, Methadone 1, Rifabutin 1 Metformin 1 Interactions No dose adjustment necessary No dose adjustment necessary No dose adjustment necessary Limit the total daily dose of metformin to 1,000 mg. When stopping DTG, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of DTG recommended Multivitamins, calcium supplements, iron supplements 1 DTG to be administered 2 hours before or 6 hours after taking these agents Magnesium/aluminium-containing antacids 1 DTG to be administered 2 hours before or 6 hours after taking these agents Carbamazepine, rifampicin, efavirenz; nevirapine and tipranavir/r 1 The recommended dose of DTG is 50 mg twice daily when co-administered with these agents. In the presence of INI resistance, combination with these agents should be avoided Note: Co-administration of dofetilide and dolutegravir is contraindicated. 1,2 1. TIVICAY Summary of Product Characteristics. September TRIUMEQ Summary of Product Characteristics. September 2015

29 Impact of ARVs on DTG exposure Co-administered drug DTG C or C 24 Geometric mean change Recommendation 1 Protease inhibitors DRV/r 600/100 mg BID* 38% No DTG dose adjustment required ATV 400 mg OD* 180% No DTG dose adjustment required ATV/r 300/100 mg OD* 121% No DTG dose adjustment required NNRTIs RPV 25 mg OD 22% No DTG dose adjustment required EFV 600 mg OD 75% DTG 50 mg BID should be given ETR 200 mg BD 88% DTG should not be given with ETR without co-administration of ATV/r, DRV/r or LPV/r NRTIs TDF 300 mg OD 8% No DTG dose adjustment required C : Trough concentration *DTG 30 mg OD studied; Unboosted ATV is not licensed in the EU; INInaive patients; alternative combinations should be considered where possible for INI-experienced patients with certain INI-associated resistance substitutions or clinically suspected INI resistance 1.Tivicay SmPC January 2014

30 DTG with ETR DTG + ETR without bpi DTG + ETR with bpi twice daily DTG 50mg qd + LPVr 400/100 bd DTG AUC + ETR 200mg bd DTG AUC 70% + DRVr 600/100 bd DTG AUC 25% Song et al. AAC 2011

31 VIIV EUROPEAN SCIENTIFIC REVIEW FORUM ON DOLUTEGRAVIR

32 ETR + MVC = MVC (600mg or 150 bd without/with PI/b) RTV + MVC = MVC (150mg bd) RTV + DTG = potentially DTG ETR + DTG = DTG

33 You plan to modify the ART regimen Which is your preferred strategy? 1. DRV/b + DTG 2. DRV/b + DTG + ETR 3. DRV/b + DTG + MVC 4. DRV/b + MVC + ETR 5. DRV/b + DTG + MVC + ETR Added TAF/FTC DTG 100mg bd

34 Thanks to Saye Khoo (UoL) David Back (UoL) Romina Quercia (ViiV) 34