Esperienze con DAA nella coinfezione HCV/HIV

Transcription

1 Esperienze con DAA nella coinfezione HCV/HIV Raffaele Bruno, MD University of Pavia Division of Infectious Diseases Fondazione IRCCS Policlinico San Matteo Pavia, Italy

2 Disclosure Advisory board a speaker: Abbvie BMS Gilead MSD

3 Outline Efficacy of DAA s in HIV- HCV coinfected patients Drug Drug interactions The Possible Association Between DAA Treatment for HCV Infection and HCC Occurence/Recurrence HBV reactivation during DAA s treatment Reinfection

4 Outline Efficacy of DAA s in HIV- HCV coinfected patients Drug Drug interactions The Possible Association Between DAA Treatment for HCV Infection and HCC Occurence/Recurrence HBV reactivation during DAA s treatment Reinfection

5 SVR rate (%) Improved SVR12/24 rates over time in HCV GT1 patients co-infected with HIV 1 10 BOC+ IFN+RBV PEG PEG+RBV 6 mo 1 12 mo 1 12 mo 1 PEG+RBV 6-12 mo 2 TVR+ PEG+RBV 6-12 mo 3 SMV+ PEG+RBV 6-12 mo 4 SOF+RBV 6 mo PHOTON-1 5 SOF+ PEG+RBV 3 mo Study OMV/PTV/RTV+ DSV+RBV 3-6 mo TURQUOISE-1 7 LDV/SOF 3 mo ION-4 8, ERADICATE 9 IFN, interferon; RBV, ribavirin; PEG, pegylated interferon; BOC, boceprevir; TVR, telaprevir; SMV, simeprevir; OMV, ombitasvir; DSV, dasabuvir; PTV, paritaprevir 1. Torriani FJ et al. N Engl J Med 2004;351: ; 2. Sulkowski M et al. Lancet Infect Dis 2013;13: ; 3. Sulkowski M et al. Ann Intern Med 2013;159:86 96; 4. Dieterich D et al. CROI P#24; 5. Sulkowski M et al. AASLD 2013; 6. Rodriguez-Torres M et al. IDWeek P#714; 7. Sulkowski M IAC 2014, Melbourne, Australia; 8. Naggie S et al. CROI Seattle, WA. #LB-152; 9. Osinusi A et al. JAMA 2015;313: ; 10. AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed July 2015

6 SVR Rates From Clinical Trials Investigating the Efficacy of DAAs in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection Wyles DL, et al. Clin Infect Dis, 2016

7 SVR Rates From Clinical Trials Investigating the Efficacy of DAAs in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection - II Wyles DL, et al. Clin Infect Dis, 2016

8 12 Week Regimen HCV Mono-Infection HCV/HIV Co-infection LDV/SOF 99% (211/214) 96% (332/355) DCV+SOF 100% (41/41) 97% (123/127) OBV/PTV/RTV+DSV 96% (455/473) 94% (29/31) +RBV (PrOD) EBR/GZP 95% (273/288) 95% (179/189) Hepatology 2017

9 COMPASSIONATE PROGRAM IN CO-INFECTED PATIENTS Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir combination treatment in co-infected HIV-HCV patients: results of a Italian compassionate use program Andreoni M et. al.clin Infect Dis Mar 1;64(5):

10 SIMIT Compassionate Use Program Monza Milano(5 Torino centri) Pavia Genova Siena Bergamo Brescia Modena Padova Ferrara Ancona Pescara 26 sites involved 26,2% F Roma (5 centri) Bari 73,8% M Napoli Salerno Catania Andreoni Adapted M et. by poster al.clin SAT-147 Infect EASL Dis. Barcellona 2017 Mar ;64(5):

11 SVR ,1 99,0 98,6 96, SVR4 EOT SVR4 SVR12 Andreoni Adapted M et. by poster al.clin SAT-147 Infect EASL Dis. Barcellona 2017 Mar ;64(5):

12 SWIFT-C: 8-Wk SOF/LDV for Pts With HIV and Acute GT1/4 HCV Coinfection Optimal duration of SOF/LDV for acute HCV infection in HIV-coinfected pts not known; previous study showed SVR12 rate of 77% with 6 wks of therapy [1] SWIFT-C: single-arm study [2] Baseline HIV regimens: boosted PI, 26%; NNRTI, 30%; INSTI, 52%; TDF/FTC, 85%; ABC/3TC, 15% Wk 8 SVR12 Pts with acute GT1/4 HCV infection and HIV coinfection (N = 27; n = 26 GT1) SOF/LDV QD (N = 27) 100% 1. Rockstroh JK, et al. Lancet Gastroenterol Hepatol. 2017;2: Naggie S, et al. AASLD Abstract 196.

13 Only 35.3% had access to HCV treatment. Despite excellent rates of SVR12 rates (91.6%), only 21% (545/2,607) of our HIV-HCV coinfected patients are cured. Icona Foundation and HepaIcona Study Group PLOS ONE May 17, 2017

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15 Outline Efficacy of DAA s in HIV- HCV coinfected patients Drug Drug interactions The Possible Association Between DAA Treatment for HCV Infection and HCC Occurence/Recurrence HBV reactivation during DAA s treatment Reinfection

16 Mechanisms of Drug Interactions of DAAs DAA Victim of DDI Perpetrator of DDI DDI Potential Glicaprevir / Pibrentasvir Substrate for CYP3A4, OATP1B1/3, P-gp, BCRP Inhibits CYP3A4, OATP1B1/3, OCT1, BCRP, P-gp, UGT1A1,. Moderate Simeprevir Substrate for CYP3A4, P-gp & OATP1B1 Inhibits gut CYP3A4, CYP1A2, OATP1B1 & P-gp Moderate Grazoprevir/elbasvir Substrate for CYP3A4, P-gp & OATP1B1 Inhibits P-gp & BCRP Moderate Daclatasvir Substrate for CYP3A4, P-gp Inhibits OATP1B1, P-gp & BCRP. Moderate Ledipasvir/sofosbuvir Substrate for P-gp & BCRP Gut ph Inhibits P-gp & BCRP Moderate/ Low Velpatasvir/sofosbuvir Substrate for P-gp & BCRP Gut ph Inhibits P-gp & BCRP Moderate/ Low Sofosbuvir Substrate for P-gp & BCRP Low Available at and relevant SmPCs ie Incivo (telaprevir), updated 27th July 2015;Victrelis (boceprevir), updated 5th March 2015;Viekirax (2D), updated 2nd Oct 2015;Exviera (dasabuvir) updated 2nd Oct 2015; Olysio (Simeprevir), updated 25th Aug 2015;Daklinza (daclatasvir), updated 30th Sept 2015;Sovaldi (sofosbuvir), updated 27th Aug 2015;Harvoni (LDV/SOF), updated 27th Nov 2015

17 EBR/GZR= Elbasvir/Grazoprevir GLE/ PIB= Glecaprevir/ Pibrentasvir LED/SOF = Ledipasvir/ Sofosbuvir

18 Outline Efficacy of DAA s in HIV- HCV coinfected patients Drug Drug interactions The Possible Association Between DAA Treatment for HCV Infection and HCC Occurence/Recurrence HBV reactivation during DAA s treatment Reinfection

19 Semantics of Hepatocellular Carcinoma (HCC) RECURRENCE: Reappearance of HCC in a subject (with or without liver disease) with a previous HCC judged to be radically cured by any technique (TACE, RFTA, resection) OCCURRENCE: De novo appearance of HCC in a subject (with or without liver disease) with no history or previous evidence of a liver tumor

20 HCV clearance on DAAs and RECURRENCE of HCC

21 Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy HCC recurrence rate was 27.6%, 3 pts died and 16 developed radiologic tumor recurrence. Overall median follow-up time after DAA was 5.7 months ( ). Median time between HCC treatment and start of DAA was 11.2 months Median time from DAA start to recurrence was 3.5 months 27.5% 72.4% Reig M. J Hepatol. 2016

22 by reanalyzing the Reig s data, a significant difference in recurrence was The recurrence of HCC is not correlated to treatment but depends on the time of assessment of found between patients wich obtained a response to ablative or resective therapy for HCC complete HCC response > 6 months before starting DAA s therapy Cammà C, Cabibbo G, Craxì A. J Hepatology 2016

23 HCV clearance on DAAs and occurrence of HCC

24 Antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy. Cheung MCM et al, Journal of Hepatology 2016: 65,

25 SVR by DAAs reduces the incidence of HCC in patients with HCV infection 77 pts SVR by DAA regimens vs 528 pts by PEG-IFN + RIBA Follow-up of 4.0 years 2.6% of DAA-treated pts developed HCC The HCC risk rate after SVR is similar independently from DAA or IFN-based regimens. Kobayashi M. J. Med. Virol. 2017

26 HCV clearance and HCC: the take-home message Sustained HCV clearance (SVR) by either IFN-based or DAA regimens minimizes the rate of progression of CHC to cirrhosis and hence reduces indirecty the risk of HCC. Once HCV cirrhosis has developed, the risk of HCC is reduced but not canceled altogether. HCV patients with cirrhosis in SVR still need regular US surveillance for HCC

27 Outline Efficacy of DAA s in HIV- HCV coinfected patients Drug Drug interactions The Possible Association Between DAA Treatment for HCV Infection and HCC Occurence/Recurrence HBV reactivation during DAA s treatment Reinfection

28 Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration Adverse Event Reporting System..immune reconstitution occurs with HCV removal, host recognition of HBV DNA probably occurs followed by vigorous host immune responses leading to liver injury (HBV flare) Bersoff-Matcha SJ, Cao K, Jason M, et al. Ann Intern Med. 2017;166(11):

29 SVR12, % LDV/SOF for 12 Weeks in HBV/HCV Co-Infection Open-label, Phase 3 study of LDV/SOF for 12 weeks in 111 Taiwanese patients with HCV GT 1 or 2 co-infected with HBV HCV HBV Baseline Demographics LDV/SOF 12 weeks N=111 Mean age, y (range) 55 (32 76) Male, n (%) 42 (38) GT 1 / GT 2, n (%) 68 (61) / 43 (39) HCV treatment experienced, n (%) 37 (33) Mean baseline HCV RNA, log 10 IU/mL (range) 5.9 ( ) Cirrhosis, n (%) 18 (16) Mean ALT, U/L (range) 68 (17 281) HBsAg positive, n (%) 110* (99) HBeAg positive, n (%) 1 (<1) HBV treatment experienced, n (%) 5 (4) Mean baseline HBV DNA, log 10 IU/mL (range) 2.1 ( ) Baseline HBV DNA <LLOQ, n (%) 37 (33) *1 patient changed HBsAg status between screening and baseline; No patients currently on HBV treatment (>6 months) 111/111 Safety LDV/SOF 12 weeks was safe and achieved 100% SVR in HCV GT 1 and GT 2 patients co-infected with HBV / 67 0 Overall Safety / Laboratory Abnormalities SVR Overall LDV/SOF 12 weeks N=111 Any AE 66 (60) Grade 3 4 AE 1 (<1) Serious AE 4 (4) DC due to AE 0 Grade (<1) 44 year old male with transient, asymptomatic G4 lipase at Week 4 unrelated to treatment. Liu, EASL 2017, PS-098

30 LDV/SOF for 12 Weeks in HBV/HCV Co-Infection n, % HBV Reactivation, Criteria Overall N=111 BL HBV DNA <LLOQ n=37 BL HBV DNA LLOQ n=74 Increase to LLOQ 31 (28) 31 (84) + ALT >2x ULN 0 0 Increase >1 <2 log 10 IU/mL 37 (33) 11 (30) 26 (35) + ALT >2x ULN 1 (<1) 0 1 (1) Increase 2 log 10 IU/mL (any visit) 24 (22) 11 (30) 13 (18) + ALT >2x ULN 4 (4) 0 4 (5) ULN: male 43 U/L; female 34 U/L. No patient had AEs of jaundice, liver decompensation, liver failure or liver transplant Treatment with LDV/SOF for 12 weeks was associated with silent HBV viral reactivation in 63% of patients (70/111) No patient experienced clinical signs or symptoms of HBV reactivation 5 (5%) patients had concomitant increase in ALT; 2 (2%) patients started HBV therapy Higher baseline HBV DNA and ALT were associated with asymptomatic clinical HBV reactivation No patient experienced clinical signs or symptoms of HBV reactivation Liu, EASL 2017, PS-098

31 Management of HCV/HBV coinfected patients Recommendations: 1) Treatment of HCV with direct-acting antivirals (DAAs) may cause reactivation of HBV. Patients fulfilling the standard criteria for HBV treatment should receive NA treatment. (Evidence level II, grade of recommendation 1) 2) HBsAg-positive patients undergoing DAA therapy should be considered for concomitant NA prophylaxis until week 12 post DAA, and monitored closely. (Evidence level II-2, grade of recommendation 2) 3) HBsAg-negative, anti-hbc positive patients undergoing DAA should be monitored and tested for HBV reactivation in case of ALT elevation. (Evidence level II, grade of recommendation 1) NA= Nucleoside/Nucleotide Analogues EASL 2017 CPG HBV, J Hepatol 2017

32 Outline Efficacy of DAA s in HIV- HCV coinfected patients Drug Drug interactions The Possible Association Between DAA Treatment for HCV Infection and HCC Occurence/Recurrence HBV reactivation during DAA s treatment Reinfection

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