Clinical Notes, management of HIV/HCV patients in real life

Transcription

1 HCV TREATMENT: OPEN QUESTIONS Clinical Notes, management of HIV/HCV patients in real life Letizia Marinaro Malattie infettive Ospedale Amedeo Di Savoia, Turin

2 11 TH RESIDENTIAL COURSE ON CLINICAL PHARMACOLOGY OF ANTIRETROVIRALS Clinical Notes TDM of Antiretrovirals In 2016 LETIZIA STILL HAVE SAME DUBTS?! LETIZIA MARINARO Dip Malattie Infettive Università di Torino Ospedale Amedeo Di Savoia

3 Therapeutic Drug Monitoring (TDM) For Antiretroviral Agents Desired concentrations range TOXICITY LACK OF EFFICACY

4 Therapeutic Drug Monitoring (TDM) For Antiretroviral Agents + Direct Acting Antivirals Agents! Desired concentrations range TOXICITY LACK OF EFFICACY

5 A real, not unusual story 0 Born in 1942, male. 0 MSM. 0 In 1999 diagnosis of both HIV and HCV (genotype 3) seropositivity. 0 With a HIV VL of 4 Log 10 copies and 651 CD4+ he started ARV (AZT/3TC+IDV) and carried on for 6 months. 0 Entered into a clinical trial structured on controlled off and on-therapy trimesters with AZT/3TC+EFV. 0 Sleeping disorders. 0 Ulcerative colitis. 0 No resitance profiles available.

6 continue 0 In 2001 attempt of HCV treatment with IFN + RBV. Suspended after 3 months for intolerance (asthenia, frequent fever, depression ). 0 ARV controlled suspension. 0 Reached his CD4+ nadir of 250 cells/µl started TDF/FTC/EFV. PCR HIV rapidly got suppressed and remained undetectable or <20 copies/ml but with episodic blips. 0 In the last years developed hypertension treated with diuretics and profilactic low-dose aspirin. 0 Microaematuria, planned 24h urin test.

7 time to treat HCV! 0 Genotype 3, wild type, IL28B rs TC (not favorable), ITPA genotype: not favorable. 0 PCR HCV: UI/mL. 0 Child-Pugh score: A5 0 Transient elastography (Fibroscan) 12 KPa, CAP 292 db/m. 0 US: epathomegaly, no focal lesions. 0 Previous treatment attempt (IFN intolerance) 0 Diuretics, low dose aspirin, TDF/FTC/EFV. 0 H 165 cm, W 70 Kg. 12-week HCV treatment 400 mg sofosbuvir, 1000 mg ribavirin, daclatasvir in line with international and Italian guidelines.

8 back to DCV PK and dosing 0 No data are vailable on DCV dosing when associated with ATV unboosted, E/C/F/TDF, all regimens with Cobi, ETV. 0 Recommendation are in some cases extrapolated from results by previous observations with different drugs (ALLY-2 study, DCV initially dosed 30 with DRV on the basis of results observed with ATV/RTV) and PBPK modeling studies. 0 No clear data are available but some evidence from ALLY-2 suggests lower DCV exposures associated to lower SVR rates.

9 before starting Daclatasvir is Substrate for CYP3A4, P-gp and inhibits OATP1B1, P-gp & BCRP. Antiretrovirals Effect on DCV DCV dose Comment Efavirenz 90 mg Moderate CYP3A4 inducers Nevirapine 90 mg? no data Etravirine 90 mg? no data Atazanavir/Rtv 30 mg Strong CYP3A4 inhibitors Atazanavir mg? no data Atazanavir/Cobi 30 mg? no data E/C/F/TDF 30 mg? no data Moderate CYP3A4 inhibitors Darunavir /Rtv 60 mg Darunavir/Cobi 60 mg? no data Lopinavir/Rtv 60 mg No interactions espected Rilpivirine 60 mg? no data

10 after all 0 EFV/TDF/FTC stopped considering DDI with DCV, EFV intolerance. 0 Started EVG/Cobi/TDF/FTC. 0 In 2 weeks started SOFOSBUVIR, RBV, DACLATASVIR 60 MG.

11 treatment period 0 Rapid HCV decay, negative from week 4. 0 Quick normalization of haepatic liver function tests. 0 Slight anaemia required reduction of RBV dose. 0 Quite good tollerability excluding mild fatigue and headhache.

12 treatment period Not all so easy. EVG/Cobi/TDF/FTC well tolerated but, at 24h U examination (previous episodes of microaematuria): BL W8 w10 1 ref U Proteins mg/24h < 300 mg/24h U Albumin mg/24h < 30 mg/24h S Crea Cl ml/min ml/min TDF trough ng/ml ng/ml EVG trough ng/ml ±250 ng/ml Cobi trough ng/ml ± 130 ng/ml DCV trough ng/ml ng/ml GS trough ng/ml na Significant 11 W: STOPS proteinuria E/C/F/TDF, partly STARTS glomerular. DTG + DRV 800/RTV BP 150/90, introduced ramipril, not well tolerated. Similar TDF exposure at BL and after DCV introduction. 1

13 PK observations

14 E/C/F/TDF EVG ng/ml COBI ng/ml TDF ng/ml T0 T1 T2 T4 T8 T24 EVG COBI TDF Ref EVG 1 Ref COBI 2 Ref TDF 3 Cmin ng/ml ±260 50± Cmax ng/ml ± ± AUCss ngh/ml ± ± Viteka Summary of Product Characteristics, Gilead Sciences Ltd, 2 Tybost Summary of Product Characteristics, Gilead Sciences Ltd,. 3 Viread Summary of Product Characteristics, Gilead Sciences Ltd, March2011..

15 E/C/F/TDF + SOF + DCV 60 mg EVG ng/ml COBI ng/ml TDF/ng/mL T0 T1 T2 T4 T8 T24 EVG COBI TDF Ref EVG 1 Ref COBI 2 Ref TDF 3 Cmin ng/ml ±260 50± Cmax ng/ml ± ± AUCss ngh/ml ± ± Viteka Summary of Product Characteristics, Gilead Sciences Ltd, 2 Tybost Summary of Product Characteristics, Gilead Sciences Ltd,. 3 Viread Summary of Product Characteristics, Gilead Sciences Ltd, March2011..

16 E/C/F/TDF + SOF + DCV 60 mg DCV ng/ml T0 T1 T2 T4 T8 T24 DCV Reference 1,2 Cmin ng/ml ( ) Cmax ng/ml AUCss ngh/ml Barco A. et Al. International Congress of Drug Therapy in HIV Infection October 2016, Glasgow, UK 2 Daklinza Summary of Product Characteristics, Bristol MyersSquibb.

17 follow-up period 0 Patient achieved SVR 12 and reached SVR Improvement of haepatic stiffness: 10 KPa after 12 weeks from EOT. 0 DTG + DRV 800/RTV effective and well tollerated. 0 Slight improvement of proteinuria, BP not well controlled.

18 DCV dosing: data from our experience, Kinetic-C study. Starting from February 2015, a multicentric observational cohort study was carried on in collaboration with San Raffaele Hospital, Milan, Ospedale Sant Andrea, Vercelli, Ospedale Maggiore Della Carità, Novara, Spedali Civili, Brescia, Ospedale S. Croce e Carle, Cuneo. 176 HIV/HCV coinfected patients were enrolled. Clinical and pharmacokinetic evaluation was conducted. 44 were treated with SOFOSBUVIR + DACLATASVIR dosed in accordance with treatment guidelines if available. With ATV 400, DCV was dosed 30 mg.

19 DCV dosing: Kinetic-C study results. Overall 233 determinantions, 4 (2;7) median, IQR for each patient. TOT: 44 pts Antiretroviral Effect on DCV DCV dose DCV trough pts n Moderate CYP3A4 inducers Efavirenz 90 mg Nevirapine 90 mg.. Etravirine 60 mg 45 (42;45) 2 Atazanavir/Rtv 30 mg 225 (181;250) 7 Strong CYP3A4 inhibitors Moderate CYP3A4 inhibitors No interactions espected Atazanavir mg 294 (62;294) 3 Atazanavir/Cobi 30 mg. E/C/F/TDF 60 mg Darunavir /Rtv 60 mg 406 ( ) 5 Darunavir/Cobi 60 mg. Lopinavir/Rtv 60 mg 715 ( ) 3 Rilpivirine 60 mg 188 (60;301) 9 No interactions espected Dolutegravir Raltegravir 60 mg 134 (96;208) 11 Concentrations expressed by geomean, IQR, ng/ml

20 DCV dosing: Kinetic-C study results. p=0,201 No significative difference in DCV concentrations if administered with E/C/F/TDF compared with DCV if associated with other antiviral agents in study.

21 DCV 60 plus E/C/F/TDF vs plus PIs p=0,358 No statistically significative difference in DCV geomean compared with DCV administered with Protease Inhibitors.

22 DCV 60 mg plus ETV p=0,018 DCV C trough was significantly lower, 45 ng/ml (42;45) if coadministrated 60 mg with ETV when compared to DCV C trough with other antiretrovirals.

23 DCV 60 mg plus DTG or RAL Higher RAL concentrations associated with lower DCV concentations p= 0,029, rho 0,685 DCV lower if coadministrated 60 mg with DTG or RAL when compared with other ARV Significantly lower compared with association with Pis o E/C/F/TDF. p=0,004

24 DCV dosing: Kinetic-C study results. Overall 233 determinantions, 4 (2;7) median, IQR for each patient. TOT: 44 pts Antiretroviral Effect on DCV DCV dose DCV trough pts n Moderate CYP3A4 inducers Efavirenz 90 mg Nevirapine 90 mg.. Etravirine 60 mg 45 (42;45) Atazanavir/Rtv 30 mg 225 (181;250) 7 2 Strong CYP3A4 inhibitors Atazanavir mg 294 (62;294) 3 Atazanavir/Cobi 30 mg. E/C/F/TDF 60 mg Moderate CYP3A4 inhibitors No interactions espected Darunavir /Rtv 60 mg 406 ( ) 5 Darunavir/Cobi 60 mg. Lopinavir/Rtv 60 mg 715 ( ) 3 Rilpivirine 60 mg 188 (60;301) 9 No interactions espected Dolutegravir Raltegravir Concentrations expressed by geomean, IQR, ng/ml 60 mg 134 (96;208) 11

25 DCV dosing: conclusions from clinical case 0 In our patient DCV administered 60 mg + E/C/F/TDF provided drug exposures comparable with that observed in our cohort with PIs +/- RTV boosting and consistent with reference values. 0 Our data suggest dosing DCV 60 mg and not to reduce it to 30 mg when co-administered with E/C/F/TDF. 0 TDF exposures were likely not affected from DCV-Pgp inhibition and remained stable before and during DCV use.

26 DCV dosing: conclusions from study results 0 DCV at the dose of 60 mg provides adeguate exposure in combination with both ATV 400 and RPV. 0 DCV concentrations of two patients treated with ETV (+MVC and RAL or TDF/FTC) were significantly lower than expected. Increased dose of DCV 90 mg is suggested if no alternative choice to ETV is available.

27 Thanks, to the organizers that gave me the chance to participate to this important event also this year, to all of you from the auditory for your attention, to all the colleagues from Amedeo Di Savoia Hospital for continuous help, nurturance, pleasant time spent together, to all the patients that keep following our requests knowing that we try our best contributing to keep their lives as fair as possible.

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