Treatment of Chronic Hepatitis C in HIV infection

Transcription

1 Treatment of Chronic Hepatitis C in HIV infection June 25, 211 Andrew Talal, MD, MPH Associate Professor of Medicine Associate Medical Director Center for the Study of Hepatitis C Weill Cornell Medical College

2 Disclosures The following disclosures are my reported disclosures related to this presentation: Vertex: Research support; speakers bureau, advisor Merck: Research support; advisor Boehringer: Review panel member Genentech: Speaker s bureau; research support Pfizer: Review panel member.

3 Presentation outline Epidemiology and evaluation of HCV in HIV/ HCV coinfection Limited data on direct acting antivirals for HCV in HIV-infected people. Limited data on drug-drug interactions between telaprevir and antiretroviral medication. 3

4 HCV: A Global Challenge

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6 Natural History of HCV Infection Exposure (Acute phase) 15% (15) 85% (85) Chronic 8% (68) 2% (17) Cirrhosis 75% (13) 25% (4) HCC Transplant Death 6

7 HCV: Who Should Be Tested? Unexplained liver disease Unexplained abnormal ALT Blood transfusion before 1992 Past or present IV drug use Unequivocal blood exposure of skin or mucous membrane History of or current hemodialysis History of intranasal cocaine use Heavy alcohol use * History of multiple sexual partners Vietnam-era service Tattooing or repeated body piercing

8 HCV Antibody Test False-positives may occur in patients with: Autoimmune hepatitis Hypergammaglobulinemia Normal liver enzymes and no risk factors for HCV Uncommon with 2 nd /3 rd generation tests False-negatives may occur in: Immunosuppressed patients (e.g., organ transplant recipients) Chronic dialysis patients Very uncommon in 2 nd /3 rd generation tests

9 Effect of HIV Coinfection on Fibrosis Progression Rates Benhamou Y, et al. Hepatology. 1999;3:154.

10 Diagnostic Evaluation of Viral Hepatitis History and Physical Examination Duration & potential route of infection Alcohol consumption Symptoms and signs of liver disease Liver biopsy Laboratory evaluation Albumin, bilirubin, PT, ALT:AST, CBC, platelets Quantitative HBV DNA or HCV RNA HCV: Genotype HBV: surface Ag, sab, core Ab, eag and eab Assessment of liver histology-is it still necessary? Noninvasive markers of hepatic fibrosis

11 Viral Hepatitis Extrahepatic Manifestations Glomerulonephritis Cryglobulinemia Vasculitis?Lymphoma Porphyria cutanea tarda Lichen planus Association with type 2 diabetes mellitus.

12 Liver Biopsy Assess liver injury Inflammation Fibrosis HBV:Stain for surface antigen and core Relationship to treatment Urgency Necessity to complete therapy Influence retreatment and maintenance therapy

13 Fibrosis Progression in HCV II-7

14 Assessment of fibrosis: Scheuer Grade/Stage Histology No or minimal activity 1 Portal inflammation 2 Mild piecemeal necrosis 3 Mod piecemeal necrosis 4 Severe piecemeal necrosis Scheuer, J Hepatol1991;13:372-4

15 Liver biopsy limitations Morbidity Invasive procedure Sampling error Limited number of measurements Mortality 1/5, of liver Biopsy size matters-2.5 cm Fibrosis assessment variability Pathologist Different scoring systems

16 Liver biopsy alternatives Fibrotest/ Fibrosure Shasta Fibrospect II Noninvasive marker indices Forn s APRI Zeremski, Talal, J Hepatol 25:43:2-5

17 Transient elastography Modified ultrasound based technique Measure of liver stiffness Ledinghen et al, JAIDS 26;41:

18 Transient elastography: Reliable detection of advanced fibrosis Ledinghen et al, JAIDS 26;41:

19 Hepatic histology assessment- 211 HCV antibody positive HCV RNA detectable (HCV genotype) Platelets >7K PT< 13.7 No ascites Bleeding diathesis Percutaneous liver biopsy Transjugular liver biopsy 2.5 cm length Experienced hepatopathologist

20 Alternatives to liver biopsy HCV antibody positive HCV RNA detectable (HCV genotype) Fibrotest/Fibrosure (LabCorp) Fibrospect (Prometheus) Low value Follow-up Liver biopsy? Treatment Moderate values Liver biopsy High values Other lab abnormalities Treatment? Upper GI endoscopy? HCC surveillance

21 Selected Targets for HCV Antivirals capsid envelope proteins protease/helicase polymerase C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 helicase NS3/NS4A Serine Protease NS5B RNA polymerase Personal communication, Pat Weber, Schering Plough,

22 Why Treat HCV? A Curable Infection Primary goal-viral Eradication Eradication possible-viral replication extranuclear Sustained viral response-absence of detectable serum or hepatic HCV RNA three or six months post treatment Secondary goal-halt Disease Progression Viral eradication enhances but not absolutely required for fibrosis regression. In absence of viral eradication, can decrease: Fibrosis progression Hepatocellular carcinoma Development of end stage liver disease

23 Patterns of HCV Response RVR EVR Week12

24 PEG-IFN/RBV Efficacy in HIV/ HCV Co-infection Study N SVR Geno 1 Geno non-1 # % # % # % Apricot / / / ACTG / / /15 73 Ribavic / / /8 44 Total / / / Torriani et al, NEJM 24;351:438-5, 2 Chung et al, NEJM 24;351:451-9, 3 Carrat et al, JAMA 24:292:

25 PEG-IFN/RBV Efficacy in HCVinfection Study N SVR Geno 1 Geno non-1 # % # % # % Manns / / / Fried / / /14 76 Total / / / HIV/ HCV / / / Manns et al, Lancet 21;358:958-65, 2 Fried et al, NEJM 22;347:975-82

26 Advance Objectives 12 or 8 weeks of telaprevir in combination with PEG-IFN/RBV in response guided treatment to standard treatment for 48 weeks.

27 Advance: Study Design T12 PR Week 12 Week 24 Week 48 Week 72 ervr+ SVR Follow up TVR + PR PR SVR ervr- PR Follow up T8PR TVR + PR Week 8 Pbo + PR PR ervr+ SVR Follow up ervr- PR Follow up SVR PR48 Pbo + PR PR Follow up SVR (T) TVR = telaprevir 75 mg q8hrs; Pbo = Placebo; PEG-IFN (P) = pegylated interferon plus ribavirin (R) 1 or 12 mg/d

28 Advance: Stopping rules Timepoint Criteria for Stopping Action Week 4* HCV RNA > 1 IU/ml D/c TVR, cont. PR Week 12 D/c all treatment Week 24-4 HCV RNA detectable D/c all treatment *Applies to telaprevir-treated patients only

29 SVR in TVR vs. PEG-RBV P<.1 Percent of patients with SVR P<.1 (271/363) (251/364) (156/361)

30 Percent of patients with virologic failure Virologic failure: Wk 8 vs. 12

31 SVR rates by Race or Ethnicity Percent of patients with SVR 244/325 22/ /316 16/26 23/4 7/28 26/35 29/44 15/38

32 TVR/PEG-IFN/RBV in HIV/HCV Week 12 Week 24 Week 48 Week 72 T12 PR48 No ARV TVR + PR PR Follow up SVR T12 PR48: (TDF/FTC/EFV or ATV/r+TDF + FTC or 3TC) TVR + PR PR Follow up SVR PR48 (control) Pbo + PR PR Follow up SVR (T) TVR = telaprevir 75 mg q8hrs; PEG-IFN (P) = pegylated interferon plus ribavirin (R) 1 or 12 mg/d Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 211. Abst. 146LB

33 Demographics and Baseline Characteristics Gender, n (%): Male Race, n(%) Caucasian Black/African American Ethnicity, n (%) Hispanic T/PR N=7 Part A No ART PR N=6 6 (86) 4 (67) 2 (29) 4 (57) 3 (43) Age, median years (range) 39 (34-51) BMI, median kg/m 2 (range) 29 (22-37) HCV RNA 8, IU/mL**, n (%) HCV Genotype Subtype*, n (%) 1a 1b HIV RNA median copies/ml (range) 7 (1) 3 (43) 4 (57) 1495 (155-53,45) CD4+ median cells/mm 3 (range) 64 ( ) 3 (5) 3 (5) 2 (33) 48 (43-65) 31 (26-37) 5 (83) 3 (5) 2 (33) 267 (25-21,95) 672 ( ) EFV/TDF/FTC T/PR N=16 16 (1) 12 (75) 3 (19) 5 (31) 48 (31-57) 24 (21-32) 13 (81) 12 (75) 4 (25) PR N=8 7 (88) 5 (62) 3 (38) 1 (12) 47 (31-53) 23 (19-29) 7 (88) 6 (75) 1 (12) Part B ATV/r + TDF + FTC/ 3TC T/PR N=14 12 (86) 12 (86) 2 (14) 3 (21) 54 (37-6) 24 (23-33) 1 (71) 11 (79) 3 (21) PR N=8 7 (88) 7 (88) 1 (12) 3 (38) 39 (26-53) 25 (22-3) 7 (88) 5 (62) 3 (38) <5 <5 <5 <5 533 ( ) 514 ( ) 492 ( ) 535 (32-772)

34 Undetectable HCV RNA at Week 4 (RVR) Percent of patients with HCV RNA Undetectable n/n = /7 12/16 9/14 /6 1/8 /8 13 No ART EFV/TDF/FTC ATV/r + TDF + FTC/3TC TVR + PR PR Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 211. Abst. 146LB

35 Undetectable HCV RNA at Week 12 (cevr) Percent of patients with HCV RNA Undetectable n/n = /7 12/16 8/14 1/6 1/8 1/8 No ART EFV/TDF/FTC ATV/r + TDF + FTC/3TC TVR + PR PR Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 211. Abst. 146LB

36 Serious Events and Treatment Discontinuation T/PR (N=7) Part A No ART PR (N=6) EFV/TDF/FTC T/PR (N=16) PR (N=8) Part B ATV/r + TDF + FTC/ 3TC T/PR (N=14) PR (N=8) Any AE 1% 83% 94% 88% 1% 1% Serious AE 14% 21% Discontinuation of all study drugs Due to AE 14% Due to anemia 7% Due to rash Mild and moderate rash events occurred in 16% and 11% of T/PR patients, respectively and in 14% and <1% of PR patients

37 Drug-drug interactions: ARV Inhibitors of CYP3A and TVR Atazanavir/ritonavir (ATV/r), darunavir/r (DRV/ r), fosamprenavir/r (fapv/r), lopinavir/r (LPV/ r). Inducer of CYP3A Efavirenz Inhibitor of CYP3A Telaprevir Boceprevir CROI abstract ##118, #119, #629, 211

38 Drug-drug interactions: ARV and TVR Neither TVR nor BOC are increased by ritonavir boosting. EFV decreases BOC concentration by 44% and also decrease TVR conc. All ritonavir boosted Pis decrease TVR conc-2% for ATV/r to 54% for LPV/r. Doses of TVR to 1125 mg TID might be needed for patients on ATV/r. 38

39 HCV Treatment in HIV/HCV coinfection Recent approval of first direct acting antivirals (boceprevir and telaprevir). Opportunities for off-label use in HIV/HCV coinfection Need depends upon urgency-fibrosis stage, extrahepatic manifestations, patient desire New opportunities for research studies: Need data on optimal management in HIV/ HCV coinfection. New treatment regimens with easier side effect profiles and dosing regimens.