Hepatitis Mini-Symposium Johns Hopkins Brazil Conference HIV/AIDS

Transcription

1 Hepatitis Mini-Symposium Johns Hopkins Brazil Conference HIV/AIDS April 15, 2016 Ashwin Balagopal, M.D. and Michael Chattergoon, M.D./Ph.D. Division of Infectious Diseases Center for Viral Hepatitis Research Johns Hopkins University

2 No relevant disclosures Disclosures

3 Hepatitis C Objectives Review HCV epidemiology Provide a clinical perspective of HIV-1/HCV co-infection To describe the indications for treating HCV infection To give an overview of new and emerging direct-acting antivirals (DAA) for HCV To describe HCV treatment in HIV-1 co-infected persons

4 Acute HCV Infection is Increasingly Recognized HET IDU MSM Non-urban Urban Suryaprasad Wandeler et et al., al., CID, CID,

5 From: The Increasing Burden of Mortality From Viral Hepatitis in the United States Between 1999 and 2007 Date of download: 1/2/2013 Copyright The American College of Physicians. All rights reserved.

6 Prevalence of Hepatitis C in Brazil Ferreira et al., Braz J Inf Dis, 2015

7 Ferreira et al., Braz J Inf Dis, 2015

8

9 Prevalence of HCV among HIV-1 infected patients in Baltimore Thomas DL, Ann Rev Med, 2007

10 Mortality from Liver Disease in HIV-1 Morbidity and mortality are still high in HIV despite effective antiretroviral therapy. Weber R et al. Arch. Intern. Med Thomas DL. Ann Reviews Med D:A:D study, AIDS Jun 2010.

11 HCV and HIV-1: Liver Related Mortality UK Hemophilia population, Liver deaths HIV fold HIV fold Risk after 10 years Liver Deaths (O/E) HIV+ HIV- GP Darby SC, et al. Lancet 1997

12 Who should we treat?

13 US GUIDELINES (IDSA/AASLD)

14 US GUIDELINES (IDSA/AASLD)

15 WHO GUIDELINES Assess liver fibrosis by AST:Platelet Ratio (APRI) or FIB-4 testing All adults and children with chronic HCV should be assessed for antiviral treatment

16 How should we treat?

17 How should we treat? Counsel patients on stopping exposure and reducing liver damage Drug treatment programs Alcohol cessation Healthy diet and exercise

18 HCV Virology Drug Development ss+ RNA with a negative strand intermediate Infects ~10-30% of hepatocytes Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. Balagopal et al, Gastroenterology 2013

19 HCV Virology Drug Development Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

20 HCV Virology Drug Development Telaprevir Boceprevir Simeprevir Paritaprevir/r itonavir Grazoprevir Ledipasvir (LDV) Ombitasvir (OMB) (Daclatasvir; DCV) Elbasvir Sofosbuvir (SOF) Dasabuvir (DSV) Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

21 HCV Virology Drug Development Telaprevir Boceprevir Simeprevir Paritaprevir/r itonavir Grazoprevir Ledipasvir Ombitasvir Daclatasvir Elbasvir (Velpatasvir) Sofosbuvir (SOF) Dasabuvir (DSV) Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

22 HCV Virology Drug Development Telaprevir Boceprevir Simeprevir Paritaprevir/r itonavir Grazoprevir Ledipasvir Ombitasvir Daclatasvir Elbasvir (Velpatasvir) Sofosbuvir Dasabuvir Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

23 How should we treat HCV mono-infection?

24 ION-1: SOF-LDV Rates of Sustained Virologic Response According to Subgroup. Afdhal N et al. N Engl J Med 2014;370:

25 AVIATOR: PAR/r/OMB + DSV ± RBV Percentage of patients achieving SVR a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450 ABT-450 ABT-450 ABT-267 ABT-267 ABT-450 ABT-267 ABT-333 RBV ABT-333 RBV RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV 8 weeks 12 weeks 12 weeks RBV Observed data ITT Treatment-naϊve patients Null Responders

26 COSMOS: SIM + SOF Lawitz E et al., The Lancet, 2014.

27 Patients, % SVR12 C-EDGE treatment-naive study: 12-week regimen of grazoprevir/elbasvir (GZR/EBR) in G1/4/6 patients 299/ /246 68/70 144/ /131 18/18 8/10 4 Non-VF Good safety and tolerability profile: No drug-related SAE; 2 deaths unrelated to drugs 1 Breakthrough Relapse Lab: No concurrent ALT/Bili increase, no anemia VF = virologic failure Zeuzem S, et al. EASL 2015, Vienna. #G07

28 SVR12 (%) GZR/EBR ± RBV for 12 weeks in G1/4 patients who previously failed PegIFN/RBV: C-EDGE treatment-experienced trial SVR according to baseline factors SVR according to BL NS3 and NS5 RAVs Total NS3 variants not detectable SVR12 n/n (%) NS3 RAVs 5-fold shift NS3 RAVs >5-fold shift G1a 95% 107/112 (96%) 104/111 (94%) 0 G1b 99% 133/135 (99%) 9/9 (100%) 1/1 (100%) NS5A variants not detectable NS5A RAVs 5-fold shift NS5A RAVs >5-fold shift G1a 95% 190/192 (99%) 10/10 (100%) 11/21 (52%) G1b 99% 127/127 (100%) 0 16/18 (89%) Kwo P, et al. EASL 2015, Vienna. #P0886 GZR/EBR FDC ± RBV was safe and effective in PR non-responders 16 weeks + RBV achieved 100% SVR in cirrhotic null responders 12/14 G1 failures had high-level NS5A RAVS at baseline An intensified regimen is needed to overcome impact of baseline NS5A RAVs, especially in G1 pts Baseline NS5A testing advisable with this regimen now that commercially available

29 Initial Treatment of HCV (US) GT1a Treatment-Naïve Elbasvir/Grazoprevir X 12 weeks (in the absence of RAVs) Same for cirrhotic patients Sofosbuvir/Ledipasvir X 12 weeks Same for cirrhotic patients Paritaprevir/ritonavir/Ombitasvir/Dasabuvir + RBV X 12 weeks Sofosbuvir + Simeprevir X 12 weeks Sofosbuvir + Daclatasvir X 12 weeks

30 NS5A Resistance Associated Variants (RAVs) M 28 A/G/T Q 30 D/E/H/G/K/L/R L 31 F/M/V Y 93 C/H/N/S

31 Initial Treatment of HCV (US) GT1a Treatment-Naive GT1b Treatment-Naive Elbasvir/Grazoprevir X 12 weeks (in the absence of RAVs) Same for cirrhotic patients Sofosbuvir/Ledipasvir X 12 weeks Same for cirrhotic patients Paritaprevir/ritonavir/Ombitasvir/Dasabuvir + RBV X 12 weeks Elbasvir/Grazoprevir X 12 weeks Same for cirrhotic patients Sofosbuvir/Ledipasvir X 12 weeks Same for cirrhotic patients Paritaprevir/ritonavir/Ombitasvir + Dasabuvir X 12 weeks Same for cirrhotic patients Sofosbuvir + Simeprevir X 12 weeks Sofosbuvir + Daclatasvir X 12 weeks

32 Initial Treatment of HCV (US) GT1a Treatment-Naive GT1b Treatment-Naive Elbasvir/Grazoprevir X 12 weeks (in the absence of RAVs) Same for cirrhotic patients Sofosbuvir/Ledipasvir X 12 weeks Same for cirrhotic patients Paritaprevir/ritonavir/Ombitasvir/Dasabuvir + RBV X 12 weeks Elbasvir/Grazoprevir X 12 weeks Same for cirrhotic patients Sofosbuvir/Ledipasvir X 12 weeks Same for cirrhotic patients Paritaprevir/ritonavir/Ombitasvir + Dasabuvir X 12 weeks Same for cirrhotic patients Sofosbuvir + Simeprevir X 12 weeks Sofosbuvir + Daclatasvir X 12 weeks NOT Recommended Sofosbuvir + RBV X 24 weeks PEG-IFN + RBV ± Sofosbuvir, Simeprevir, Telaprevir, or Boceprevir X 12 to 48 weeks Monotherapy

33 Initial Treatment of HCV (WHO July, 2015) Sofosbuvir + Ribavirin ± Pegylated Interferon Genotypes 1, 2, 3, 4 Simeprevir + Ribavirin + Pegylated Interferon Pegylated Interferon + Ribavirin + Telaprevir or Boceprevir Pegylated Interferon + Ribavirin

34 What s available in Brazil? Pegylated Interferon Ribavirin Sofosbuvir (GT1, 2, 3, 4) Simeprevir (GT1 and 4) Daclatasvir (GT1 and 3) Ombitasvir, Veruprevir/r, Dasabuvir (GT1) Private sector

35 How should we treat HCV in HIV-1 co-infection?

36 From: Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV Copyright 2012 American Medical Association. All rights reserved. Limketkai et al., JAMA

37 From: Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV Copyright 2012 American Medical Association. All rights reserved. Limketkai et al., JAMA

38 Effect of ART on Liver Disease Progression in HCV Co-infection Variable Person-Years Events HR (95% CI) Total No initiation Referent ART initiation ( ) No initiation Referent <2 y since initation ( ) 2 to <4 y since initiation ( ) 4 y since initiation ( ) Anderson JP et al., CID, 2014

39 From: Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV JAMA. 2012;308(4): doi: /jama Date of download: 1/2/2013 Copyright 2012 American Medical Association. All rights reserved.

40 Sofosbuvir + Ledipasvir in HIV-1/HCV Co- Infection Osinosi et al., JAMA, 2015

41 TURQUOISE-1 HIV-1 co-infected GT1 + Tx-naïve or experienced +/- cirrhosis Paritaprevir/ritonavir NS3/protease inhibitor Ombitasvir - NS5A inhibitor Dasabuvir - Non-nucleoside polymerase inhibitor Ribavirin or 24 weeks Sulkowski et al., JAMA, 2015

42 Patients (%) C-EDGE co-infection: Phase 3 study of GZR/EBR in patients with HCV/HIV SVR12 207/ /144 42/44 27/28 Lost to f/u or d/c unrelated to VF Breakthrough Relapse Reinfection Rockstroh JK, et al. EASL 2015, Vienna. #P0887

43 Overall (N=153) Patient demographics G Baseline disease characteristics Baseline immune status cart regimen ALLY-2: DCV + SOF for treatment of HCV G1 4 in HIV/HCV coinfection ALLY-2 (DCV + SOF) SVR12 and 95% CI for key subgroups 97% Male n=135 Female n=18 Age <65 years n=145 Age 65 years n=8 White n=97 Black/African-American n=50 G1a n=104 G1b n=23 G2 n=13 G3 n=10 G4 n=3 HCV RNA <2 x 10 6 IU/mL n=52 HCV RNA 2 x 10 6 IU/mL n=101 HCV RNA <6 x 10 6 IU/mL n=91 HCV RNA 6 x 10 6 IU/mL n=62 Cirrhotic n=24 Non-cirrhotic n=124 IL28B genotype: CC n=41 IL28B genotype: non-cc n=112 <200 CD4 cells/mm 3 n= CD4 cells/mm 3 n= CD4 cells/mm 3 n=94 Boosted PI-based n=70 DRV-RTV n=30 Non-nucleoside-based n=40 Other n=41 Overall (N=335) Patient demographics G Baseline disease characteristics Prior HCV Tx Baseline CD4 ART regimen Male Female Black Non-black BMI <30 kg/m 2 BMI 30 kg/m 2 1a 1b 4 <800,000 RNA 800,000 RNA Non-cirrhotic Cirrhotic CC CT TT No Yes <350 cells/mm cells/mm 3 EFV + FTC + TDF RAL + FTC + TDF RPV + FTC + TDF ION-4 (LDV + SOF 12 weeks) Wyles D, et al. EASL 2015, Vienna. #LP01; Cooper C, et al. EASL 2015, Vienna. #P EFV: Efavirenz; FTC: Emtricitabine; TDF: Tenofovir; RAL: Raltegravir; DRV: Darunavir; RPV: Rilpivirine

44 Patients (%) ALLY-2: DCV + SOF for treatment of HCV G1 4 in HIV/HCV coinfection SVR12 ( ) ( ) ( ) ( ) ( ) ( ) 80/83 31/41 43/44 98/101 38/50 51/52 Naive 12 weeks Naive 8 weeks Experienced 12 weeks 1 f/u Wk 12 missing 1 detectable at EOT 1 relapse 10 relapsers 2 f/u Wk 12 missing 1 relapse DCV + SOF x12 weeks is highly effective in HIV-infected pts including black pts Flexible administration with ART Lower SVR w/8 weeks suggest HIV has an impact when the regimen is shortened Wyles D, et al. EASL 2015, Vienna. #LP01

45 Initial Treatment of HCV in HIV-1 Co-infection

46 Initial Treatment of HCV in HIV-1 Co-infection Drug-Drug Interactions ART Interruption is NOT recommended Ledipasvir Tenofovir (Avoid when CrCl < 60 ml/min) Tenofovir + Boosted PI (Avoid) Sofosbuvir-Ledipasvir Cobicistat Elvitegravir Tipranivir Sofosbuvir Tipranivir CrCl <30 ml/min Paritaprevir/ritonavir/Ombitasvir/Dasabuvir Patients must be on ART Efavirenz Rilpivirine Darunavir Lopinavir/r Simeprevir Efavirenz Etravirine Nevirapine Cobicistat HIV-1 PIs

47 Initial Treatment of HCV in HIV-1 Co-infection ART Interruption is NOT recommended Ledipasvir Tenofovir (Avoid when CrCl < 60 ml/min) Tenofovir + Boosted PI (Avoid) Sofosbuvir-Ledipasvir Cobicistat Elvitegravir Tipranivir Sofosbuvir Drug-Drug Interactions Tipranivir CrCl <30 ml/min Paritaprevir/ritonavir/Ombitasvir/Dasabuvir Patients must be on ART Efavirenz Rilpivirine Darunavir Lopinavir/r Simeprevir Efavirenz Etravirine Nevirapine Cobicistat HIV-1 PIs Can use Together Paritaprevir/ritonavir/Ombitasvir + Dasabuvir Rategravir (and Dolutegravir?) Enfurvitide Tenofovir Emtricitabine Lamivudine Atazanavir Ritonavir When boosting PI, dose may need to be adjusted or held Administer with the fixed-dose HCV drug Simeprevir Raltegravir (and Dolutegravir?) Rilpivirine Maraviroc Enfurvitide Tenofovir Emtricitabine Lamivudine Abacavir

48 Hepatitis B Objectives Epidemiology, basic virology, natural history Hepatitis B monoinfection in immunocompetent patient HIV-HBV coinfection Hepatitis B with immunosuppressive therapy HBV-HCV co-infection with HCV treatment

49 Global Burden of HBV Disease WHO global HBV estimates ~ 2 billion people infected with HBV ~ 248 million people have chronic HBV ~ 800,000 deaths annually caused by HBVrelated liver disease or HCC 15% to 25% risk of early death caused by liver cancer or end-stage liver disease among patients with chronic HBV infection WHO. Hepatitis B fact sheet, July 2015; Schweitzer A et al, Lancet 2015 epub July 28

50 Hepatitis B is the leading cause of viral hepatitis deaths, 2010 E Slide courtesy of WHO

51 Phases of chronic HBV HBsAg HBsAg+ HBsAg- HBV DNA HBeAg/anti-HBe HBeAg+ Anti-HBe+ ALT/hepatitis Immune Phase Tolerant Active Inactive Immune Clinical Asymptomatic (wks-years) Symptoms (wks: selflimited or years: chronic) Inactive (may last lifetime; risk of reactivation) Recovery (anti-hbs) Exposure

52 TREATING HBV MONOINFECTION IN IMMUNOCOMPETENT HOST

53

54 Baseline HBV DNA predicts risk of cirrhosis Serum HBV DNA (copies/ml) Total Patients Cases of Cirrhosis Adjusted RR* (95% CI) P Value HBeAg-Negative Patients < 10 4 (~2000 IU/ml) (reference) to < ( ) < (~20,000 IU/ml) ( ) <.001 HBeAg-Positive Patients < ( ) NS 10 4 to < ( ) < (~20,000 IU/ml) ( ) <.001 * Adjusted for gender, age, anti-hcv levels, smoking, and alcohol use. NS, not significant Chen CJ, et al. J Hepatol 2005;42(Suppl 2):16.

55 Who to treat Treatment criteria Preferred initial therapy Other considerations Immune active (HBeAg pos or neg) ALT > 2x ULN* or significant liver disease PLUS HBeAg NEG: HBV DNA > 2000 IU/mL or HBeAg POS: > 20,000 IU/mL PEG-IFN, entecavir, TDF If ALT > ULN but below threshold, then consider [1] age (>40 y), [2] liver disease stage, [3] extrahepatic manifestations Cirrhosis Any detectable HBV DNA Entecavir, TDF *30 U/L males and 19 U/L females. AASLD guidelines Hepatol Jan 2016

56 In whom to defer treatment Definition Management Immune tolerant ALT ULN* HBV DNA usually > 1 million IU/mL No liver disease Test ALT q 6 mos for progression to active disease Inactive chronic hepattis B HBsAg +, HBeAg - ALT <ULN*, HBV DNA <2000 IU/mL (usu undetect) Test ALT q 6 months for reactivation *30 U/L males and 19 U/L females. Adapted from AASLD guidelines Hepatol Jan 2016

57 Drugs approved to treat hepatitis B L-nucleoside group Lamivudine Telbivudine (Emtricitabine) Acyclic phosphonate group Adefovir dipivoxil Tenofovir disoproxil fumarate D-cyclopentane group Entecavir Interferons Interferon-alpha and pegylated IFN-alpha

58 Potency Potency versus genetic barrier to resistance of HBV drugs LdT ETV TDF LAM FTC ADV IFN Genetic Barrier M. Levrero (2006)

59 Factors influencing choice of Tenofovir vs. Entecavir Favors Tenofovir Existing LMV-resistant mutations Failing L-nucleoside HIV co-infection Favors Entecavir Renal insufficiency-existing or high risk

60 Cumulative incidence of drugresistant HBV Adapted from EASL Guidelines 2012 J Hepatol

61 Tenofovir alafenamide non-inferior to TDF for hepatitis B Significantly smaller decrease in hip and spine BMD and smaller increase in egfr with TAF Gilead press release, Jan 2016

62 When to stop therapy HBeAg positive HBeAg negative peg-ifn 48 weeks 48 weeks Nucleos(t)ide analogues Non-cirrhotics HBsAg loss consider 12 months after HBeAg seroconversion (very low evidence) Cirrhotics: indefinite Can consider with HBsAg loss otherwise indefinite Cirrhotics: indefinite AASLD guidelines 2016

63 HIV-HBV CO-INFECTION

64 Who to treat in HIV-HBV co-infection Initiate HAART in HIV-HBV co-infected patients (AII) CrCl > 60: TDF (TAF) with Lamivudine or Emtricitabine preferred CrCl 30-60: TAF with Lamivudine or Emtricitabine preferred CrCl < 30: Entecavir + fully suppressive ART (BIII) If HAART not initiated and HBV DNA >2000 IU/mL with ALT >2x ULN (AI), options are PEG- IFN alfa or adefovir (CIII) DHHS guidelines UptoDate

65 HBV REACTIVATION WITH IMMUOSUPPRESSION

66 Rituximab black box warning about HBV reactivation Initial U.S. Approval: 1997 WARNING: FATAL INFUSION REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY See full prescribing information for complete boxed warning. Fatal infusion reactions within 24 hours of Rituxan infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor patients and discontinue Rituxan infusion for severe reactions (5.1). Severe mucocutaneous reactions, some with fatal outcomes (5.2). Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death (5.3). Progressive multifocal leukoencephalopathy (PML) resulting in death

67 Rheumatology patients taking anti-tnf 4800 patients in Kaiser system with anti-tnf Reactivations: 17% of HBsAg+, and 0.03% with resolved hep B (Pauly MP et al, AASLD 2011, Abstract 72) Retrospective study of 179 Italians with resolved hep B and no preventive HBV therapy (Barone et al, Hepatol :40-46) Rituximab (n=14), anti-tnf (n=146), anti-il-1, anti- IL-6, CTLA4-Ig with & without prednisone (<7.5 mg) No reactivations (median f/u > 34 months) Risk increased when anti-tnf agents combined with other immunosuppressive agents

68 Algorithm for prophylaxis with anti-tnf therapy Perrillo Hepatol (1)

69 HBV reactivation with immunosuppression Abrupt increase in HBV replication Can lead to fulminant hepatitis and death Mortality rates up to 25% (Loomba et al, Ann Int Med 2008) Common in HBsAg + patients ~50% with high immunosuppressive regimens Occurs less frequently in anti-hbc+, anti- HBs + ~5% with high immunosuppressive regimens

70 Approach to patient receiving chemotherapy HBsAg + Anti-HBc + HBV DNA HBV DNA Detectable Meets treatment criteria Treat Undetectable Does not meet treatment criteria Preventive therapy Detectable Preventive therapy Undetectable Preventive therapy if B-cell depletion, stem cell or organ transplant. Otherwise HBV DNA monitoring Modified from DiBisceglie et al, Hepatol :703 and Cheung KS, Hepatol Int 2016 Jan Lok and McMahon, AASLD guidelines, Hepatol, Dec 2009