HIV Infection with HCV Future Directions

Transcription

1 HIV Infection with HCV Future Directions Dr Ranjababu (Babu) Kulasegaram Consultant Physician in HIV/GU Medicine Guy s and St Thomas NHS Foundation Trust London, UK

2 Presenter disclosure information Dr Ranjababu Kulasegaram has received grants and research support from MSD, abbvie, BMS, ViiV, Gilead, Boehringer Ingelheim and Janssen. He has also undertaken speaker, advisory board and consultancy work for ViiV,MSD, Abbott, BMS, Jannsen and Gilead

3 Objective Background - Natural History and epidemiology Impact of HIV on HCV Impact of HCV on HIV Treatment options now Future

4 Background HIV HCV DNA HIV1 and 2 - subtypes virions / day Mutation rates Long-lived proviral reservoir Potential cure No effective vaccine RNA Genotypes and subtypes virions /day Mutation rates No integration Cure (SVR) No effective vaccine

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6 Epidemiology

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8 Where we are with HIV

9 Cause of death in Treated HIV Swiss HIV cohort study (449 deaths) from Non-AIDs caused 85% of deaths HCV infection played an important role M Ruppik et al, Abs: 789

10 Patients are growing older 100% % of patients per age category 80% 60% 40% 20% <30 years years years >50 years Year Adapted from: Swiss Cohort Study 2013 Update. Available at Last Accessed Jul 2013

11 Co-morbidities in HIV+ vs HIV- people Polypathology prevalence among patients and control subjects Cases 1% 3% 16% 80% 40 yrs n=542 Prevalence 3.9% 1% 8% 31% 60% yrs n=1, % 6% 17% 35% 42% yrs >60 yrs n= % 4% 15% 29% 31% 21% n= % 100% 75% 50% 25% 0% 0% 1% 9% 90% 40 yrs yrs n=1, % 0% 2% 17% 80% n=5, % 1% 6% 28% 65% yrs n=1, % 0.25% 2% 15% 42% 40% >60 yrs n= % Controls No age-related diseases 1 co-morbidity 2 co-morbidities 3 co-morbidities HIV+ patients are more likely to n n Guaraldi G et al. Clin Infect Dis 2011;53: Develop co-morbidities earlier Suffer from multiple illnesses concurrently 4 co-morbidities

12 Impact of HIV on HCV

13 Natural history of HCV infection Resolved Exposure (Acute phase) 15% (15) 85% (85) Stable Chronic 80% (68) Slowly Progressive 20% (17) Cirrhosis 75% (13) HIV and Alcohol 25% (4) HCC Transplant Death Metabolic syndrome Alter MJ Semin Liver Dis 1995; 15: Management of Hepatitis C NIH Consensus Statement 1997; March 24-26:15(3).

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15 Stop Cirrhosis / Extra Hepatic manifestations

16 Pineda, J A, Romero-Gómez, et al. Hepatology 2005; 41: HCV mono-infected vs HIV(+)/HCV(+) Outcome of cirrhosis after 1 st decompensation Survival Years HCV 74 HCV/HIV

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18 Impact of HCV on HIV

19 Effects of HCV on HIV Disease Meta-analysis involving 6216 patients from 8 trials n Mean increase in CD4 cell count among was 33.4 cells/mm 3 less than that observed in HIVmonoinfected patients EuroSIDA n After adjusting for baseline factors, investigators concluded that HIV/HCV-coinfected patients do not have a greater risk of progressing to AIDS n ARV Liver toxicity Miller et al. CID. 2005;41: Rockstroh et al. JID. 2005;192:

20 Acute HCV in HIV MSM transmission

21 LGV N = 1993 cases since 2003 Acute HCV E Bottieau et al. Eurosurveillance, 2010; 15, 39 (15), 30 September 2010

22 Case review Patient 1: 45 year-old MSM n HIV n CD4 nadir 350 n Atripla n CD4 513 (35%) HIV RNA <20 copies/ml n Acute HCV Sept 2013 n Genotype 1a n???

23 Acute HCV - When to initiate Treatment Diagnosis of acute HCV (HCV RNA positive) Week 4 Decay HCV RNA < 2 log 10 reduction Treat Week 8 HCV RNA >2log10 reduction rebound Treat further decay Week 12 HCV RNA positive Treat negative repeat HCV RNA according to local protocol

24 What next? He wants treatment now

25 HCV Direct-Acting Antiviral (DAA) DAAs* IFN + RBV Triple therapy TVR + PR BOC + PR FDV + PR IFN TIW Peg-IFN + RBV SOF + PR SMV + PR SOF + RBV (IFN-intolerant or ineligible) *For genotype 1 TIW: three times per week SMV: simeprevir; SOF: sofosbuvir; FDV: faldaprevir

26 Importance of weight-based Ribavirin (1000mg <75kg/1200mg >75kg) Soriano, et al. AIDS :

27 Triple therapy in HIV/HCV DAA NS3/4A Telaprevir (TVR) + PR Boceprevir (BOC) + PR Simeprevir (SMV)+ PR Faldaprevir (FDV)+ PR

28 Study 110: HCV-treatment-naïve patients SVR rates 24 weeks post treatment (SVR24*) Randomised, double-blind, placebo-controlled trial in 62 patients receiving/not receiving ARV: TVR + PR vs placebo + PR for 12 weeks followed by PR to week 48 No ART EFV/TDF/FTC ATV/r/TDF/FTC or 3TC Total SVR (%) 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22 *Patient was defined as SVR24 if HCV RNA was <LLOQ in the visit window ART: antiretroviral therapy; LLOQ: lower limit of quantification Sulkowski MS, et al. Ann Intern Med 2013;159:86 96

29 Study 110: AEs and premature discontinuations due to AEs 1 TVR treatment Phase (Weeks 1 12) Overall treatment Phase (Weeks 1 48) AEs TVR/PR (n=38) PR (n=22) Difference (95% CI) TVR/PR (n=38) PR (n=22) Difference (95%CI) Overall Any AE 37 (97) 21 (95) 2 ( 8, 12) 38 (100) 22 (100) - AEs leading to death 0 (0) 0 (0) - 0 (0) 0 (0) - Serious AEs 2 (5) 0 (0) 5 ( 2, 12) 7 (18) 2 (9) 9 ( 8, 26) AEs leading to treatment discontinuation 2 (5) 0 (0) 5 ( 2, 12) 3 (8) 0 (0) 8 ( 1, 16) Special interest Pruritus 13 (34) 1 (5) 30 (12, 47) 15 (39) 2 (9) 30 (11, 50) Rash 11 (29) 4 (18) 11 ( 11, 32) 13 (34) 5 (23) 11 ( 12, 35) Anemia 5 (13) 4 (18) 5 ( 24, 14) 7 (18) 4 (18) 0.2 ( 20, 20) Anorectal discomfort 5 (13) 1 (5) 9 ( 5, 22) 5 (13) 2 (9) 4 ( 12, 20) Overall safety and tolerability profile of TVR combination therapy was comparable with that previously observed in chronic genotype 1 HCV mono-infected patients 1,2 Discontinuation of TVR only due to AE, n=1 (due to jaundice); discontinuation of all study 1. Sulkowski MS, et al. Ann Intern Med 2013;159:86 96 drugs due to AE (overall treatment phase),n=2 (due to cholelithiasis and hemolytic anemia) 2 2. Sherman KE, et al. Hepatology 2011;54(Suppl. S1). Abstract LB-8

30 BOC + PR for the treatment of HCV treatment-naïve coinfected patients: virologic response over time Phase II, randomised, double-blind (BOC), open-label (PR) trial in 98 patients receiving ARV: 4 week PR lead-in then BOC + PR (vs placebo + PR) for 44 weeks PR BOC+PR Patients with undetectable HCV RNA (%) n/n= 3/64 3/34 27/64 5/34 38/64 8/34 47/64 11/34 42/64 10/34 40/64 9/34 40/64 10/34 Sulkowski M, et al. Lancet Infect Dis 2013; 13:

31 Simeprevir (SMV/TMC435) Single-pill, once-daily, oral HCV NS3/4A protease inhibitor approved in Japan, Canada, and the US, and under regulatory review in Europe and other regions Multigenotypic: antiviral activity in patients infected with HCV GT1, 2, 4, 5, and SMV is being investigated in IFN-free combinations In Phase III trials of SMV + PR in GT1 HCV mono-infected patients, SVR12 rates of 80 81% (treatment-naïve patients) and 79% (relapsers to IFN-based treatment) were reported 5 7 Safe and well tolerated (~3,800 patients treated to-date) GT, genotype; IFN, interferon; PR, peginterferon-α + ribavirin; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment 1 Reesink HW et al. Gastroenterology 2010;138: ; 2 Moreno C et al. J Hepatology 2012;56: ; 3 Fried MW et al. Hepatology 2013: epub; 4 Zeuzem S et al. Poster LB-2998 presented at EASL 2011; 5 Manns M et al. Oral presentation at EASL 2013; 6 Jacobson I et al. Poster 1425 presented at EASL 2013; 7 Forns et al. Gastroenterology In press

32 C212 study design: Phase III, open-label, single-arm, international trial HCV treatment-naïve Prior relapse a Prior partial response a Prior null response a Cirrhotic patients (F4) RGT b Week SMV 150 mg/ PR SMV 150 mg/ PR SMV 150 mg/ PR PR PR PR Follow-up Primary analysis Follow-up 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) PR, peginterferon-α2a + ribavirin; RGT, response-guided treatment; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment Dieterich D. et al., Oral presentation at CROI 2014

33 C212: SVR12 Primary endpoint and versus historic PR-only control (ITT population) p<0.001 a SMV/PR Historical PR p<0.001 a SVR12 (%) b /106 n/a n/a n/a 42/53 51/176 13/15 7/10 16/28 2/37 Overall Naïves Relapsers Partial Null 5 c a Formal hypothesis testing was used (one-sample single-sided z-test) to allow comparison of primary efficacy variable with historical data for naïves and null respo b From PEGASYS USPI, co-infected patients; c From INCIVEK TM USPI, mono-infected patients; n/a, not applicable ITT, intent-to-treat; PR, peginterferon-α2a + ribavirin; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment

34 C212: SVR12 by IL28B genotype (ITT population) CC CT TT 27/28 40/59 11/18 15/15 19/27 8/10 7/7 6/6 1/1 5/7 1/2 4/5 10/19 2/4 *0/2 patients; SVR12, sustained virologic response at 12 weeks after planned end of treatment

35 C212: Conclusions SMV QD + PR led to high SVR12 in HCV GT1/HIV-1 patients regardless of prior HCV treatment response, with overall rates of 74% (range: 57 87%) Baseline characteristics did not have an impact on SVR12 rates: METAVIR fibrosis score, HCV GT1 subtype, presence of Q80K polymorphism and baseline CD4+ count 89% of treatment-naïve and prior relapsers without cirrhosis met RGT criteria and were eligible to shorten therapy to 24 weeks, with 87% achieving SVR12 HIV virologic suppression was maintained during SMV therapy SMV QD + PR was well tolerated with a safety profile similar to that observed in mono-infected patients Only 1.9% (2/105) of patients had Grade 3 hemoglobin or bilirubin abnormalities All rash and pruritus AEs were Grade 1 or Grade 2 and none were considered serious. No Grade 3 or Grade 4 rash or pruritus AEs were reported. AE, adverse event; GT, genotype; PR, peginterferon-α2a + ribavirin; RGT, response-guided therapy; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment

36 Background Faldaprevir (FDV) is a potent inhibitor of HCV NS3/4A, with antiviral activity against HCV genotypes (GT) 1, 4, 5, and 6 in vitro 1 FDV is a substrate of CYP3A4, a moderate inhibitor of CYP3A4 at 240 mg QD 2, and a weak inhibitor of CYP3A4 at 120 mg QD The Phase III STARTVerso4 trial evaluated the safety and efficacy of FDV + pegylated interferon α-2a / ribavirin (PR) in patients co-infected with HCV and HIV White PW, et al. Antimicrob Agents Chemother 2010;54: ; 2. Sabo J, et al. ICAAC 2012; Abstract A-1248.

37 Study design rationale FDV with ART (in healthy subjects) Change in FDV AUC 1 FDV with darunavir/ritonavir FDV with efavirenz 130% 35% ART regimen No ART Raltegravir or maraviroc based Efavirenz based Darunavir/ritonavir or atazanavir/ritonavir based RANDOMIZED ALLOCATED FDV dosage 120 or 240 mg QD 240 mg QD 120 mg QD 37 ART, antiretroviral therapy; AUC, area under the curve; FDV, faldaprevir; QD, once daily. 1. Sabo J, et al. CROI 2013; Abstract 35.

38 Study design Large, multicenter, open-label, sponsor-blinded, randomized, Phase III study in patients co-infected with HCV GT-1 and HIV-1 ARM A (N=123) a FDV 120 mg QD + PR 24 weeks ETS: NO ETS: YES PR 24 weeks STOP TREATMENT ARM B (N=187) a FDV 240 mg QD + PR 12 weeks FDV 240 mg QD + PR, 12 weeks PR, 12 weeks ETS: NO ETS: YES PR 24 weeks STOP TREATMENT Day 1 Wk 12 Wk 12 Wk 24 Wk 24 Wk 48 FDV dose: randomization (1:1) or allocation according to ART ETS: HCV RNA <25 IU/mL at Week 4 and undetectable at Week 8 Re-randomization (1:1) Primary endpoint: SVR12 38 a Number randomized/allocated. ART, antiretroviral therapy; ETS, early treatment success; FDV, faldaprevir; PR, pegylated interferon α-2a and ribavirin; QD, once daily; SVR12, sustained virologic response (HCV RNA <25 IU/mL, not detected) 12 weeks after the planned end of treatment.

39 Conclusions FDV was highly efficacious and well tolerated in difficult-to-treat patients co-infected with HIV and HCV GT-1 Treatment with FDV resulted in a total SVR12 rate of 72% A high proportion of patients (80%) achieved early treatment success (ETS) and 86% of these patients achieved SVR12 High SVR12 rates achieved regardless of HCV genotype Presence of compensated cirrhosis FDV doses and durations studied Among patients with ETS, 24 weeks total duration of therapy was possible without compromising SVR12 rates The safety profile of FDV in HIV and HCV GT-1 coinfected patients was similar to that observed in HCV GT-1 mono-infected patients 1, Jensen DM, et al. AASLD 2013; Poster 1088; 2. Jacobson IM, et al. CROI 2013; Poster 1100.

40 NS5B Sofosbuvir

41 SOF + PegIFN + RBV in Treatment-Naïve HIV/HCV Co-infected Patients Phase 2 Study 1910 Design Single-centre, 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 41

42 SOF + PegIFN + RBV in HIV/HCV Coinfection SVR12 According to HCV Genotype and HIV ARV Regimen HCV RNA <LLOQ (%) /19 13/ /4 1/1 2/2 1/1 GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 SVR12 (%) /9 7/8 6/6 FTC/TDF + Protease Inhibitor FTC/TDF + NNRTI 100 FTC/TDF + Raltegravir Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714 NNRTI, non-nucleoside reverse transcriptase inhibitor 42

43 Short Duration of SOF + PegIFN + RBV x 12 Weeks Comparison of HCV Mono-infected to HIV/HCV Co-infected SVR12 (%) NEUTRINO (HCV Mono- infected) Study 1910 (HIV/HCV Co- infected) Similar response rates in HIV/HCV co-infected patients compared with 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 43

44 All oral HCV

45 All-Oral Therapy of SOF + RBV Comparison of HCV Monoinfected to HIV/HCV Coinfected SVR12 (%) GT 1 SOF + RBV 24 weeks SVR12 (%) GT 2 SOF + RBV 12 weeks SVR12 (%) GT 3 SOF + RBV 12 weeks SVR12 (%) GT 3 SOF + RBV 24 weeks SPARE PHOTON- 1 0 VALENCE PHOTON- 1 0 FISSION PHOTON- 1 0 VALENCE Similar response rates observed in HIV/HCV coinfected patients compared with HCV monoinfected patients Osinusi A, et al. JAMA. 2013;310(8): Sulkowski MS, et al. AASLD Washington, DC. Oral #212. Zeuzem S, et al. AASLD Washington, DC. #1085. Lawitz E, et al. N Engl J Med May 16;368(20):

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48 TURQUOISE- I (M14-004) Phase 3 trial, randomized, open- label design Genotype 1, HIV- 1- HCV co- infected subjects (N=300) Primary endpoint: SVR 12 3 DAAs + RBV PaIent PopulaIon GT Treatment Arms HIV- 1- HCV co- infected a 1 Arm 1: ABT- 450/r/ABT ABT RBV for 12 weeks Arm 2: ABT- 450/r/ABT ABT RBV for 24 weeks a Co- infected subjects had a plasma HIV- 1 RNA <40 copies/ml during screening and were on a stable HIV- 1 an\retroviral therapy regimen NCT ClinicalTrials.gov Web site: hap:// Updated October 18, Accessed November 27, 2013.

49 On-treatment Viral Response to MK-5172/ MK-8742 ± RBV for 12 Weeks in HCV/HIV- Coinfected Patients: The C-WORTHY Study Mark Sulkowsky et al CROI 2014 #654LB

50 Aim and study design To compare on-treatment HCV RNA responses (defined as proportion of patients with HCV RNA <25 IU/mL) in HIV/ HCV GT1 co-infected patients treated with MK MK-8742 ± RBV with those in HCV mono-infected patients 50 Adapted from: Mark Sulkowsky et al CROI 2014 #654LB

51 Virologic Responses: Intent to Treat (Full Analysis Set) Population 51 Adapted from: Mark Sulkowsky et al CROI 2014 #654LB

52 Summary Efficacy All co-infected and mono-infected patients had an HCV RNA <25 IU/mL independent of RBV by week 4 of therapy HCV kinetics over the first 4 weeks of therapy were similar in patients with and without HIV co-infection with G1a or G1b infection Two co-infected subjects with low PK levels of MK-5172 and/or MK-8742 experienced virologic breakthrough at TW8 both cases with low blood levels of MK-5172 and/or MK-8742) Safety The safety profile of MK-5172/MK-8742 was comparable among mono- and coinfected patients The most common AEs in co-infected patients were fatigue and headache All co-infected patients had suppressed HIV and stable CD4 counts There were no early discontinuations due to drug-related adverse events 52 Adapted from: Mark Sulkowsky et al CROI 2014 #654LB

53 BMS AI (ALLY2): phase 3, open- label, randomised efficacy study of daclatasvir and sofosbuvir in pa\ents co- infected with HIV Treatmentnaive 12 weeks DCV 30, 60 or 90 mg QD + SOF 400 mg QD 24-week follow-up Treatmentnaive 8 weeks DCV 30, 60 or 90 mg QD + SOF 400 mg QD 24-week follow-up Treatmentexperienced 8 weeks DCV 30, 60 or 90 mg QD + SOF 400 mg QD 24-week follow-up Week 0 Week 8 Week 12 Week 20 Week 24 (SVR (SVR ) 12 ) 12 Week 36 (SVR 24 ) DCV, daclatasvir; SOF, sofosbuvir; SVR, sustained virologic response Pa\ents Es\mated enrolment: 200 Treatment naive or experienced HCV/HIV co- infected Status: Recrui\ng Country USA GT1 6 NCT

54 Stop Cirrhosis / Improve QOL

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57 HIV/HCV HIV stable HCV Liver health, Fibrosis (can you wait, how long) Co-morbidity (renal, Metabolic, BMI, Mental health) Readiness/choice Success (SVR) Safety, drug-drug interactions (polypharmacy) Trial options Timeline Team approach Access 57

58 Sick & dying in early 80s to long term chronic illness How did we achieve it - mid 90s HAART-ARVs community response & Government listens Global access Testing, TasP (Zero transmission) MTCT PEP & PEPSE PrEP

59 HCV - IFN Peg IFN, Peg IFN + RBV, All oral DAA Access, affordable HCV Testing, Cure HCV and care Liver health - Follow up, HCC, Liver Transplant HCV free world HIV free world (ZERO Transmission) Stigma (Education) Treat HIV reduce transmission Cure HCV, reduce cirrhosis, HCC, ESLD and improve QOL Not just a virus We can do it, work together

60 Thank You

61 Thank You