Overview on latest data on IFN-sparing and IFN-free regimens in HCV/HIV patients 10th HIV and hepatitis coinfection workshop June 2014 Paris, France

Transcription

1 Overview on latest data on IFN-sparing and IFN-free regimens in HCV/HIV patients 10th HIV and hepatitis coinfection workshop June 2014 Paris, France Patrick Ingiliz, Berlin

2 Conflicts of Interest Boards, Consulting, Teaching, Travel: Gilead, Janssen-Cilag, Roche, MSD, Abbvie, BMS, Boehringer- Ingelheim Coinvestigator in clinical trials: Roche, Vertex, Janssen-Cilag, MSD, Gilead, BMS, Boehringer- Ingelheim, ViiV, Abbvie

3 New online EASL HCV recommendations Indications for HCV treatment in HIV/HCV co-infected patients are identical to those in HCV mono-infection (A1) Same treatment regimens can be used in HIV/HCV patients as in patients without HIV infection, as the virological results of therapy are identical (A1) EASL recommendations April

4 Overview over current/upcoming DAA-free regimens in coinfection......basically the same as in HCV monoinfection: SOF-RBV SIM-SOF SOF-DAC 3D-RBV SOF-LDV-FDC...whatever comes next: ASV/DCV/-325, MK-5172/8472, etc.

5 Are there particularities in HIV-HCV coinfection? Drug-drug interactions Acute HCV infection Fast fibrosis progresion Reinfection

6 Peg+RBV+HCV PI: DDI with ART P/R/TVR P/R/BO C P/R/SMV P/R/FDV P/R/TVR P/R/BOC P/R/SMV P/R/FDV NRTIs Protease Inhibitors Zidovudine a a a a Stavudine b b b b Didanosine b b b b Lamivudine Emtricitabine Abacavir c c c c Tenofovir NNRTIs Lopinavir/r Fosamprenavir/r Atazanavir/r Darunavir/r Integrase Inhibitors Raltegravir Dolutegravir Nevirapine???? Efavirenz Etravirine? Rilpivirine Elvitegravir/COBI???? Entry Inhibitors Maraviroc 150mgBID 150mg BID Combination possible Combination possible under reserve Combination not recommended or contra-indicated a b c Increased risk of anemia Increased risk of lactic acidosis in association with ribavirin Interaction possible with ribavirin, but no proof of lesser efficacy Use hep-druginteractions.org!!

7 Combination not recommended or contra-indicated Interferon/Ribavirin-free DAA combos: DDI with ART DCV SOF SMV DCV SOF SMV NRTIs Zidovudine Stavudine Didanosine Lamivudine Emtricitabine Abacavir Protease Inhibitors Lopinavir/r 30 Fosamprenavir/r 30 Atazanavir/r 30 Darunavir/r 30 Integrase strand Inhibitors Tenofovir NNRTIs Nevirapine??? Efavirenz 90 Etravirine? Rilpivirine Raltegravir Dolutegravir Elvitegravir/C?? Entry Inhibitors Maraviroc Use hep-druginteractions.org!! Combination possible Combination possible under reserve

8 Acute HCV in HIV patients Medical Center for Infectious Diseases, Berlin: ~1500 HIV+, 218 cases of acute HCV 2002 to 10/ cases in HIV-, 4 female, 32 reinfections Steininger K, Ingiliz P et al., not yet published

9 What do we know about DAAs in acute HCV? change ARVs TVR + pifn+rbv Follow-up Weeks ETR SVR 4 SVR 12 SVR 24 Total 16/19 16/19 16/19 16/19 Succes s rate 84% 84% 84% 84% Ongoing/upcoming trials acute HCV/HIV: DAHHS, Holland: BOC-P-R, 12 weeks CHAT-Study, Germany: TVR-P-R, 12 weeks Swift-C, USA: SOF-R, 8 vs 12 weeks SOF/LDV, Europe, 6 weeks SOF/LDV, US: 12 (8) weeks Fierer et al., CID 2014

10 EASL HCV recommendations: Acute hepatitis C Although no data is available yet, IFN-free regimens can theoretically be used in these patients and are expected to achieve high SVR rates. The same doses and durations as for patients with chronic hepatitis C must be used, until new data indicate whether shorter and/or less intensive treatment is sufficient to achieve high infection cure rates. (Recommendation B1) EASL Recommendations 2014

11 Is there an evidence for fast fibrosis progression after unsuccesful treatment? Boesecke C et al., CROI 2014

12 Insulin resistance Alcohol Illicit drugs HIV HCV GT3 GT1, 4 Steatosis SREBP1 Drug toxicity IRIS NASH Lactic acidosis Fibrosis STAT1 PPARγ Steatosis HIV ART HIV ART ART Lipodystrophy/dyslipidemi a/ insulin resistance/metabolic syndrome Ingiliz P, Lemoine M, Benhamou Y, 2011

13 Philip, actor, Berlin 2011: 35 year old, homosexual male HIV infection CDC B3 (2002, MSM) History of secondary syphilis, 3x 5x gonorrhea, 2x chlamydia No others concomitant illnesses Party drugs, moderate drinker

14 HIV/ARV history CD4 nadir: 180/μL, HIV-PCR c/ml no opportunistic infections ARV: CBV+TDF+LPV/r STI TDF/FTC + FPV/r 2005-now no resistance-associated mutations 2011 CD4: 1009/μL (40%), HIV-PCR <50 c/ml

15 Another year, another STD Sept. 2004: chlamydial urethritis, ALT 55 U/mL. No other clinical symptoms Syphilis negative, HBV negative HCV Ab negative HCV-PCR: 2.3mio IU/mL HCV genotype 1a acute sexually acquired HCV infection

16 HCV treatment history 2004 acute HCV: Pegα-2a + RBV (800mg) 24 weeks: RVR, EoTR: Relapse 2 nd treatment 2005: Pegα-2b + RBV (1.000mg) Stop at week 24: null response (HCV RNA reduction <2log) 3rd treatment 2008: Pegα-2a + RBV (1.200mg) Stop at week 12, null response (HCV RNA reduction <2log) Boesecke, Curr Opin HIV AIDS, 2011

17 HCV cirrhosis within 7 years: a coinfection reality 11/2011: Genotyp 1a, IL28B C/T HCV-VL: IU/ml, ALT 1,5x ULN FibroScan, : 26,3 KPa = consistent with liver cirrhosis Ultrasound: no direct signs of liver cirrhosis, no lesion, no ascites, spleen 13cm EGD: no esophageal varices Liver biopsy : nodular liver cirrhosis with minimal inflammatory activity and mild steatosis Retreatment in study C212: Simeprevir+PEG+RBV

18 C212 study design: Phase III, open-label, single-arm, international trial HCV treatment-naïve Prior relapse a RGT b Week SMV 150 mg/pr SMV 150 mg/pr PR PR Follow-up Follow-up Prior partial response a Prior null response a Cirrhotic patients (F4) SMV 150 mg/pr PR Follow-up Antiretrovirals permitted during SMV therapy: lamivudine, emtricitabine, tenofovir, abacavir, rilpivirine, enfuvirtide, raltegravir, maraviroc Primary endpoints: SVR12, safety and tolerability Secondary endpoints: virologic response at other time points, meeting RGT criteria b for shortened treatment to 24 weeks, on-treatment failure, viral relapse a After prior PR treatment; b RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable) at Week 4 and undetectable at Week 12 (measured using Roche COBAS TaqMan HCV/HPS assay, v.2) Dieterich et al. CROI Abstract 24.

19 C212: SVR12 by METAVIR fibrosis score (ITT population) METAVIR F0 F2 METAVIR F3 F4 SVR12 (%) /45 14/22 24/27 4/7 7/9 2/2 1/2 2/3 4/7 6/10 Overall Naïves Relapsers Partial Null ITT, intent-to-treat; SVR12, sustained virologic response 12 weeks after end of treatment Dieterich et al. CROI Abstract 24.

20 Primary Analysis C212 Study: Response-guided Therapy Allows Shortened Treatment Duration with High SVR12 Patients without cirrhosis meeting RGT criteria: 89% (54/61) of patients eligible for 24 weeks of treatment met RGT criteria 41/48 treatment-naïve patients 13/13 prior relapsers Proportion of patients achieving SVR12 Proportion of patients, % 47/54 36/41 11/13 RGT, response-guided treatment in HCV treatment-naïve or relapse patients; SVR12, sustained virologic response 12 weeks after end of treatment Dieterich et al. CROI Abstract 24.

21 Response pattern in a cirrhotic P/R-null-responder Baseline HCV VL IU/mL Day 3: HCV VL IU/mL Day 7: HCV VL 914 IU/mL Day 14: HCV VL <25 IU/mL, TD Day 28: HCV VL <25 IU/mL, TD Week 12: HCV VL TND Week 24: HCV VL TND Week 48: HCV VL TND No side effects

22 Baseline HCV VL IU/mL Day 3: HCV VL IU/mL Day 7: HCV VL 914 IU/mL Day 14: HCV VL <25 IU/mL, TD Day 28: HCV VL <25 IU/mL, TD Week 12: HCV VL TND Week 24: HCV VL TND Week 48: HCV VL TND Week 60: HCV VL TND Week 72: HCV VL IU/ml

23 Relapse or reinfection? Lab results 05/2013: ALT 32 U/L, AST 34 U/L, γgt 32 U/L, total bilirubin: 0.45 mg/dl HCV-Genotyp 1a HCV-RNA IU/mL platelets 152/nL PT 98% albumin 45 g/l Hb 14,0 g/dl Phylogenetic analysis C/E1: different virus: reinfection (study lab comfirmed)

24 Reinfection an alarming reality! 553 patients from 7 NEAT centers with cured acute HCV since 6/ with at least one reinfection (25.5%) 1509 patient-years of FU, median 2.1 years Incidence rate: 7.82/100 patient-years Treated patients: 7.9/100 patient years Spontaneous clearers: 3.3/100 patient-years Ingiliz et al., EASL 2014, Martin et al., AIDS 2013

25 Question What would you do next (06/2014 in Germany)? 1.) Treat with SOF/P/R 2.) Treat with SOF/R 3.) Treat with SMV/P/R 4.) Wait for DCV/P/R 5.) Treat with SIMSOF 6.) Wait for SOFDAC 7.) Wait for SOF/LDV-FDC 8.) Wait for other options 9.) No more treatment

26 SOF + PegIFN + RBV in Treatment-Naïve HIV/HCV Co-infected Patients Phase 2 Study 1910 Design Single-center, open-label, single-arm trial to assess the safety and efficacy of a 12-week course of SOF + PegIFN + RBV for the treatment of patients with chronic HCV, co-infected with HIV Week HCV GT 1 4 Treatment-naïve, on stable HIV ARV N=23 SOF 400 mg QD + PegIFN alfa-2a 180 µg/week + RBV mg/day No response guided therapy SVR4 SVR12 SVR24 Primary endpoint Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714

27 Short Duration of SOF + PegIFN + RBV x 12 Weeks Comparison of HCV Mono-infected to HIV/HCV Co-infected SVR12 (%) Similar response rates in HIV/HCV co-infected patients compared to HCV mono-infected patients Lawitz E, et al. APASL Singapore. Oral #LB-02 Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714

28 PHOTON-1: Study Design Wk 0 Wk 12 Wk 24 Wk 36 Wk 48 GT 1 TN SOF + RBV, n=114 GT 2/3 TN GT 2/3 TE SOF + RBV, n=68 SOF + RBV, n=41 SVR 12 SVR 24 Broad inclusion criteria Cirrhosis permitted with no platelet cutoff Hemoglobin: 12 mg/dl (males); 11 mg/dl (females) Wide range of ART regimens allowed Undetectable HIV RNA for >8 weeks on stable ART regimen Baseline CD4 count ART treated: CD4 T-cell count >200 cells/mm 3 and HIV RNA < 50 c/ml ART untreated: CD4 T-cell count >500 cells/mm 3 Naggie et al. CROI Abstract 26.

29 All-Oral Therapy of SOF + RBV in Treatment-Naïve HIV/HCV Coinfection PHOTON-1 Virologic Response HCV RNA < 25 IU/mL (%) SOF + RBV x24 weeks SOF + RBV x12 weeks SOF + RBV x12 weeks 96 GT /114 87/114 Week 4 EOT SVR12 HCV RNA < 25 IU/mL (%) GT /26 22/23 23/26 Week 4 EOT SVR An all-oral regimen of SOF + RBV for weeks resulted in high SVR12 rates in TN HIV-infected patients with GT 1, 2 and 3 coinfection with SVR12 rates similar to mono-infection No HCV resistance (S282T) was observed in virologic failures via deep sequencing Two patients had HCV breakthrough; both had documented non-adherence to SOF Two patients had transient HIV breakthrough; both had documented non-adherence to ART HCV RNA < 25 IU/mL (%) GT 3 100/100 41/41 39/40 28/42 67 Week 4 EOT SVR12 Sulkowski MS, et al. AASLD Washington, DC. Oral #212

30 SVR12 in HCV Mono-infected and HCV/HIV Co-infected All-Oral SOF+RBV x 12 or 24 weeks SVR12 (%) GT 1 SOF + RBV 24 weeks 68 76* SVR12 (%) GT 2 SOF + RBV 12 weeks 88 SVR12 (%) GT 3 SOF + RBV 12 weeks 67 SVR12 (%) GT 3 SOF + RBV 24 weeks 85 94* 20 0 SPARE 1 HCV PHOTON-1 2 HCV/HIV 20 17/25 87/114 68/73 23/26 102/183 28/42 212/250 16/17 0 VALENCE 3 HCV PHOTON-1 2 HCV/HIV 20 0 FISSION 4 HCV PHOTON-1 2 HCV/HIV Similar response rates in HCV/HIV co-infected patients compared to HCV mono-infected patients 20 0 VALENCE 3 HCV PHOTON-1 5 HCV/HIV SVR12 from VALENCE includes pooled analysis from all patients (treatment-naïve and experienced) by genotype and duration of therapy *GT1 SVR24 of 75%; GT3 TE SVR24 of 88% 1. Osinusi A, et al. JAMA. 2013;310(8): Naggie S, et al. CROI Boston, MA. Oral # Zeuzem S, et al. AASLD Washington, DC. # Lawitz E, et al. N Engl J Med May 16;368(20): SOVALDI [PI]. Gilead Sciences, Inc. Foster City, CA December 2013

31 PHOTON 2: SOF Phase 3 Study in HIV/HCV Co-infection GS-US GT 1 treatment naïve (TN) and GT 2/3 TN and treatment experiences (TE) and GT 4 subjects Week GT 2 TN SOF+RBV, n=50 SVR12 GT 2/3 TE SOF+RBV, n=50 SVR12 GT 1/3/4 TN SOF+RBV, n=170 SVR12 Study being conducted in Europe and Australia HIV treatment status Stable approved ART with CD4 >200 cells/mm 3 ; or No ART with CD4 >500 cells/mm 3 (up to 10%) Enrollment complete Clinicaltrials.gov NCT

32 Sofosbuvir/Ledipasvir in patients with HIV/HCV coinfection Fifty HIV/HCV genotype 1, treatment-naive subjects, HAI fibrosis stage 0 3 Wk 0 Wk week follow up ARV Untreated (n=13) CD4 count stable + HIV RNA <500 copies OR - CD4 count > 500 cells/mm 3 SVR 12 SOF/LDV (400/90mg) ARV Treated (n=37) - CD4 count > 100 cells/mm 3 - HIV RNA < 40 copies - Current ARVs 8 weeks SVR 4 ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine and raltegravir Osinusi et al, EASL 2014 Interim results

33 Sofosbuvir/Ledipasvir response rates ARV - 13/ 13 13/13 13/ 13 12/12 10/10 10/10 ARV + 37/37 37/37 30/30 22/22 Osinusi et al, EASL 2014

34 Sulkowski et al, EASL 2014 Phase 2: Protease + NS5A-Inhibitor +/- Ribavirin

35 12 weeks PI + NS5A in coinfected patients Sulkowski et al, EASL 2014 ART: Stable raltegravir-based regimen

36 Sulkowski et al, EASL 2014

37 Incomplete list of ongoing/upcoming trials for HIV/HCV-coinfected patients Ally 2: Sofosbuvir/Daclatasvir, all genotypes, 8-12 weeks Turquoise-1: 3D/RBV, genotype 1, weeks C-EDGE: MK-5172/MK-8742, genotypes 1, 4-6, 12 weeks ION-4: SOF/LDV, genotypes 1 and 4, 8-12 weeks ANRS: SOF/LDV, Tx-experienced, genotype 1, 24 weeks

38 Thank you for your attention Acknowledgements: Medical Center for Infectious Diseases, Berlin: Axel Baumgarten, Andreas Carganico, Stephan Dupke, Ivanka Krznaric, Martin Obermeier, Robert Ehret, Hauke Walter, Gordon Weinberg, Andreas Wienbreyer, Daniela Behrendt, Janina Motsch, Marcel Schütze, Tine Steininger University of Bonn: Jürgen Rockstroh, Christoph Boesecke, Jakob Nattermann

39