HIV/HCV coinfection. Jürgen K. Rockstroh, Department of Medicine I, Bonn University Hospital, Bonn, Germany

Transcription

1 HIV/HCV coinfection Jürgen K. Rockstroh, Department of Medicine I, Bonn University Hospital, Bonn, Germany

2 Conflict of Interest Honoraria for lectures and/or consultancies from Abbott, AbbVie, Bionor, BMS, Cipla, Gilead, Janssen, Merck, Roche, ViiV. Research grants from Dt. Leberstiftung, DZIF, NEAT ID.

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4 Burden of HIV/HCV co-infection 37 million HIV infected 2.3 million co-infected with HCV North America ~1.6 million ~32, Latin America (South & Central America, Caribbean) ~1.8 million ~18, MSM Western & Central Europe ~1 million ~14, Middle East & North Africa 24, ~54, South, West, East & Central Africa 26 million ~43, HCV co-infected Eastern Europe & Central Asia ~1.5 million ~68, HIV only East Asia 82, ~19, South & South-East Asia 3.1 million ~29 Western Pacific ~74, ~115, Heterosexual IDUs % 2% 4% 6% 8% 1% IDU: injecting drug user; MSM: men who have sex with men Platt L, et al. Lancet Infect Dis 216; doi: 1.116/S (15)485-5

5 Acute outbreaks of HCV have been reported in HIV+ MSM across the world Canada 1 51 cases UK 4,5 589 cases Belgium 1 69 cases Germany cases Swiss cases France 7 29 cases Denmark cases The Netherlands 8,9 127 cases Japan cases USA 2,3 44 cases Korea 15 3 cases Lebanon 13 1 case Taiwan cases Hong Kong cases Australia cases Total number of cases reported in the literature from these countries 1. Burchell AN, et al. Can J Infect Dis Med Microbiol 215;26:17 22; 2. Luetkemeyer A, et al. J Acquir Immune Defic Syndr 26;41:31 6; 3. Cox A, et al. Gastroenterology 29;136:26 31; 4. Giraudon I, et al. Sex Transm Infect 28;84:111 5; 5. Ruf M, et al. Euro Surveill 28;13:1 3; 6. Vogel M, et al. Clin Infect Dis 29;49:317 8; 7. Gambotti L, et al. Euro Surveill 25;1:115 7; 8. Urbanus A, et al. AIDS 29;23:F1 F7; 9. Arends JE, et al. Neth J Med 211;69:43 9; 1. Bottieau E, et al. Euro Surveill 21;15:1 8; 11. Rauch A, et al. Clin Infect Dis 25;41:395 42; 12. Barfod TS et al. Scand J Infect Dis. 211;43:145 8; 13. Dionne-Odom J, et al. Lancet Infect Dis 29;9:775 83; 14. Nishijima T, et al. J Acquir Immune Defic Sundr 214;65:213 7; 15. Lee S, et al. Korean J Intern Med 216; doi: 1.394/kjim ; 16. Sun YH, et al. J Clin Microbiol 212;5:781 7; 17. Lin AWC, et al. J Int AIDS Soc 214;17:19663; 18. Matthews GV, et al. Clin Infect Dis 29;48:65 8

6 HCV seroconversion Patient * * * * * * * testing for anti-hcv may not be enough after a first positive HCV-RNA 37% anti-hcv positive 3 months later 86% anti-hcv positive 6 months later 5% without seroconversion after 1 year Thomson et al. AIDS 29, 23:89 93

7 Cumulative incidence HCV Disease Progression Remains Faster in Coinfected Patients, Despite Effective ART.2 HCV-monoinfected patients (n=679) Antiretroviral-treated patients coinfected with HIV/HCV (n=428) x Time to hepatic decompensation (years) p<.1 Adapted from: Lo Re 3rd V, et al. Ann Intern Med 214;16:

8 Cumulative incidence Cumulative incidence HCV Disease Progression Remains Faster in Coinfected Patients, Despite Effective ART.2 HCV-monoinfected patients.2 HCV-monoinfected patients Antiretroviral-treatment patients coinfected with HIV/HCV: HIV RNA level < 1 copies/ml Antiretroviral-treatment patients coinfected with HIV/HCV: HIV RNA level > 1 copies/ml Antiretroviral-treatment patients coinfected with HIV/HCV: CD4 count <.2 x 1 9 cells/l Antiretroviral-treatment patients coinfected with HIV/HCV: CD4 count 1 9 cells/l Time to hepatic decomposition (years) Time to hepatic decomposition (years) If HIV RNA <1 copies/ml: +65% excess risk If HIV RNA >1 copies/ml: +82% excess risk If CD4 < 2/mm 2 : +23% excess risk If CD4 > 2/mm 2 : 56 63% excess risk ART, antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus. Adapted from: Lo Re 3rd V, et al. Ann Intern Med 214;16:

9 Treatment of chronic hepatitis C, including patients without cirrhosis and patients with compensated (Child-Pugh A) cirrhosis EASL 216 Guidelines, Sept.22,216

10 HCV life cycle New HCV virion HCV virion Endocytosis Cyclophilin A inhibitor 4 Inhibition of cyclophilin A reduces HCV replication NS3 inhibitor 2 Inhibits activity of NS3 protease Prevents processing of HCV proteins required for replication -previr CD81 Cytoplasm Liver cell ER Adapted from reference 1 SR-B1 Cytoplasm Nucleus Uncoating RNA replication NS4A NS4B Virion assembly ER Lumen Adapted from reference 2 Maturation Golgi PEG-IFN lambda 3 Type III pegylated interferon Expression of receptor is more limited than Alfa, should lead to improved tolerability and safety NS5B inhibitor(s) 2 Inhibits NS5B RNA replicase Prevents replication of viral genome -buvir NS5A inhibitor 2 Inhibits activity of NS5A, a multifunctional protein Prevents viral replication -asvir 1. Manns MP, et al. Nat Rev Drug Discov 27;6: Rice C. Top Antivir Med 211;19(3): Donnelly R, et al. Trends Immunol 211;32(9): Gallay P, Lin K. Drug Des Devel Ther 213;7:15-15.

11 216 EASL Guidelines Journal of Hepatology 217;66:

12 SVR 12(%) DAA Really Similarly Effective in HIV Coinfection? GECCO Cohort (9 German centres) n= mono-, 349 coinfected Liver cirrhosis 29% (31% vs. 22%) Overall-SVR 95%, 95% monoinfected, 94% coinfected SVR12 According to CD4 and Cirrhosis Status ,2 9,9 88,4 82,8 CD4 35 CD4 <35 CD4 35 CD4 <35 Non-cirrhotic Cirrhotic SVR lower in pts. with CD4 <35/µl and liver cirrhosis Boesecke C, et al. 24th CROI; Seattle, WA; February 13-16, 217. Abst. 551.

13 SVR12 (%) SVR12 in GT 1 HIV/HCV Coinfected Patients Treated with LDV/SOF for Weeks: Clinical Trials Compared to Real-World Cohorts Clinical Trials 96% 98% 1% 98% Real World Cohorts 91% 91% 98% ION 4 Study * ERADICATE * ANRS HC31 SOFTRI ** TRIO Cohort 1,2 * ASCEND 2 ** VA USC 1,2 ** Portugal 1 ** ITT analysis in GT1 patients; *ITT analysis; ** Per Protocol; ¹ ±RBV; ² small number of patients may have received 8 weeks of LDV/SOF Naggie S, et al. 67th AASLD; Boston, MA; November 11-15, 216; Abst. 892.

14 Check for DDIs between HCV and HIV drugs! Drug interactions List of CYP substrates, inhibitors, inducers HIV drug interactions Khoo S. 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 214 [oral presentation]. CYP, cytochrome

15 Low potential for drug drug interactions with some HCV DAA and HIV antiretrovirals Gilead Sciences is not responsible for the content of third party websites. DDI: drug drug interaction; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor Regularly updated Information on DDIs can be found at: EASL Recommendations on treatment of hepatitis C. Available at: (accessed September 216) DDI: drug drug interaction; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor

16 SVR12 (%) High SVR in adult patients with HIV/HCV coinfection treated with DAAs 1 ALLY-2: 1 GT 1 4, TN & TE SOF + DCV ION-4: 2 GT 1 or 4, TE & TN LDV/SOF 1 96 TURQUOISE-1, part 2: 3 GT 1 or 4, TN and TE OMV/PTV/RTV + DSV ± RBV 97 1 C-EDGE: 4 GT 1, 4 or 6, TN GRZ/EBV /11 51/52 TN TE 12 weeks 322/3 217/ weeks 12 or 24 weeks 21/ Weeks 1. Wyles D, et al. N Engl J Med 215;373:714 25; 2. Naggie S, et al. N Engl J Med 215;373:75 13; 3. Rockstroh JK, et al. IAS 216; Abstract # 1333; 4. Rockstroh JK, et al. Lancet HIV 215;2:e Studies included non-cirrhotic and cirrhotic patients. TE: treatment-experienced NOT HEAD-TO-HEAD COMPARISONS

17 SVR12 (%) ASTRAL-5: high SVR across genotypes 1 4 in adult HIV/HCV coinfected patients treated with 12 weeks SOF/VEL ASTRAL-5: HIV/HCV co-infected Treatment-naïve and -experienced, non-cirrhotic and cirrhotic GT 1 4 adults relapse 1 LTFU 1 LTFU 1 withdrew consent 2 11/16 63/66 11/12 11/11 11/12 5/5 Total 1a 1b Genotype Brau N, et al. IAS 216; Abstract #78 Error bars represent 95% confidence intervals. LTFU: lost to follow-up

18 SVR12 (%) ASTRAL-5: high SVR across all patient types in adult HIV/HCV co-infected patients treated with 12 weeks SOF/VEL ASTRAL-5: HIV/HCV co-infected Treatment-naïve and -experienced, non-cirrhotic and cirrhotic GT 1 4 adults /16 Total 82/87 19/19 71/75 3/31 No Yes Naïve Experienced Cirrhosis status Treatment history Brau N, et al. IAS 216; Abstract #78 Error bars represent 95% confidence intervals

19 DAAs were well-tolerated in clinical trials of HIV/HCV co-infected patients Adverse events common across all DAA regimens in HIV/HCV co-infection trials ALLY-2 DCV + SOF N=23 ION-4 LDV/SOF N=335 TURQUOISE-I Part 2 OMV/PTV/RTV + DSV ± RBV N=228 C-EDGE CO-INFECTION GRZ/EBV N=218 ASTRAL-5 SOF/VEL N=16 Fatigue 17% 21% 23% 13% 25% Headache 11% 25% 14% 12% 13% Diarrhoea 7% 11% 14% 7% 8% Nausea 13% 1% 2% 9% 7% D/C due to AE 2 (2%) Wyles D, et al. N Engl J Med 215;373:714 25; Rockstroh JK, et al. IAS 216; Abstract # 1333; Naggie S, et al. N Engl J Med 215;373:75 13; Rockstroh JK, et al. Lancet HIV 215;2:e319 27; Brau N, et al. IAS 216; Abstract #78 NOT HEAD-TO-HEAD COMPARISONS This table illustrate adverse events obtained between different regimens from different studies and are therefore not directly comparable as study populations are NOT matched

20 SVR 12 (%) SVR 12 (%) Real Life DAA Data from Germany: GECCO Cohort 1346 patients from 9 centres: 21% HIV/HCV co-infected, 29% F4 fibrosis/cirrhosis Pretreatment F4 Diabetes HIV-HCV yes no 459/57 379/ / /723 53/61 851/947 2/218 74/79 175/191 24/26 5/5 13/13 13/15 26/28 2 SL8 all Good response rates also in Tx experienced, F4, diabetics, coinfected HIV- HCV F4 PPI High VL Pretreatment 8 weeks of SOF/LDV very effective even in problematic patients Christensen S, et al. 23rd CROI; Boston, MA; February 22-25, 216. Abst. 584.

21 Number of Patients Dutch Athena Cohort Rapid and early treatment uptake of DAAs Since 11/215 unrestricted access to DAA Early treatment initiation in n=736 7% cure - Jan HCV Infected Never treated Unsuccessfully treated with DAA Unsuccessfully treated with (PEG-)IFN +/- BOC or TVR Currently on treatment Treatment with DAA Treatment with (PEG-) IFN +/- BOC or TVR Retained in care Ever treated Treatment completed SVR Boerekamps A, et al. 24th CROI; Seattle, WA; February 13-16, 217. Abst. 136.

22 Dutch Acute HCV in HIV Study (DAHHS; 8 Centres) Declining Acute HCV epidemic Due to DAA? 214 A-HCVn=93 PYFU n= /1PYFU (95% CI 9-14) 1.1% per year 216 A-HCVn=49 PYFU n= /1PYFU (95% CI 4-7),55% per year IRR.49 (95% CI ) Jan-Dec /1 Jan-Jun /1 Jul-Dec /1 BUT: 41% Increase in Syphilis Cases in 216 vs. 215 Boerekamps A, et al. 24th CROI; Seattle, WA; February 13-16, 217. Abst. 137LB.

23 Re-treatment after failure to LDV/SOF 9 patients without SVR in ION-4 after 12 weeks of LDV/SOF Wk Wk 12 Wk 24 Wk 36 LDV/SOF Failure N=9 LDV/SOF + RBV SVR12 GT NS5A RAVs Before Primary Study (%) NS5A RAVs at Virologic Rlapse After Primary Study (5) 1a None None Yes 1a None None Yes 1a L31M (>99), H58D (92) L31M (>99), H58D (92) Yes 1a Y93F (1), Y93N (1) Y93N (<99) Yes 1a L31M (>99), Y93N (<25) L31M (>99), Y93N (>99) Yes 1a* None Y93N (>99) Yes 1b Y93H (>99) L31I (11), Y93H (>99) Yes 1b None L31V (>99) Yes 1a None L31M (>99) No SRV12 SVR in 8/9 1 relapse 4 weeks after EOT: GT1a, no cirrhosis Cooper C, et al. 23rd CROI; Boston, MA; February 22-25, 216. Abst. 573.

24 GEHEP 2 Spanish HCV/HIV Cohort HCC after DAA therapy 319 HCV/HIV patients with HCC from 32 Spanish centres 45% pretreated HCC after median months after SVR No increased HCC recurrence rate after SVR 1% n HCC After SVR/Total n HCC 8% p <.1* 6% 4% 2% 1 (16,7%) 16 1 (9,9%) (9%) ,7%) % < Oct 214 Oct Total HCC Cases N=6 N=161 N=111 N=41 Merchante N, et al. 24th CROI; Seattle, WA; February 13-16, 217. Abst. 139.

25 Frequency of HCC Diagnosis After SVR in HIV/HCV Coinfected Patients with Cirrhosis 19 centers from the GEHEP-2 cohort reported data of the number of HIV/HCV-coinfected patients with cirrhosis who achieved SVR in each period % 15 11,72 N=135 HIV/HCV cirrhotic with SVR before January ,66 5 1,68,88 IFN PEG-IFN + RBV DAA + PR DAA IFN free HCC after SVR No. with SVR Merchante N, et al. 24th CROI; Seattle, WA; February 13-16, 217. Abst. 139.

26 HCV Reinfection Incidence and Outcomes Among HIV-positive MSM in Western Europe Incident infection 1 st Reinfection Number included Number reinfected (%) N/A 149 (24.6) Median time (years) to reinfection (IQR) N/A 1.8 ( ) Genotypes (%) G1: 376(7.5) G2: 13(2.4) G3: 46(8.6) G4: 96 (18) G1: 14(73.2) G2: 1(.7) G3: 12(8.5) G4: 25(17.6) Genotype switches (%) N/A 71/136 (52.2) Median age at reinfection (IQR) 39 (34-44) 41 (37-45) Median CD4 at reinfection 553 (412-76) Proportion with suppressed HIV VL 91/111 (82.%) Spontaneously cleared proportion 111/65 (18.3%) 21/135 (15.6%) Martin T, et al. 51st EASL; Barcelona, Spain; April 13-17, 216. Abst. PS6 Ingiliz P et al. J Hepatol treated with 87 achieving SVR (78%)

27 Chronic hepatitis and HIV: implications for care HIV infected individuals with HCV coinfection remain at higher risk for fibrosis progression and hepatic decompensation Therefore HCV therapy is prioritized in most guidelines in this patient group The short- and mid-term effects of ART on the progression of HCVrelated liver disease largely outweigh the potential risks for longterm toxicity. HIV therapy needs to consider coadministration with all oral DAA combination therapy and possible drug interactions as well as potential dose modifications with advanced liver disease. Strategies beyond administration of DAA therapy are needed to prevent HCV reinfection in HIV-coinfected individuals HCV elimination in HIV-coinfected populations appears targetable