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HEPATITIS B AND C

HEPATITIS B AND C . Dr. J ürgen K. Rockstroh Department of Internal Medicine I University Hospital Bonn Germany. 380 million HBV- infected subjects worldwide. Dienstag JL, et al. N Engl J Med 2008;359:1486–500. Hepatitis delta in HIV- infected individuals in Europe.

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HEPATITIS B AND C

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  1. HEPATITIS B AND C Dr. Jürgen K. Rockstroh Department of Internal Medicine I University Hospital Bonn Germany

  2. 380 million HBV-infectedsubjectsworldwide Dienstag JL, et al. N Engl J Med 2008;359:1486–500

  3. Hepatitis delta in HIV-infectedindividuals in Europe Soriano V, et al. AIDS 2011;25:1987–92 The EuroSIDA study was analysed for anti-HDV in chronic HBsAg positive/HIV carriers: • Prevalence of anti-HDV: 14.5% • HDV increases the risk of liver-related deaths and mortality in HIV patients

  4. HIV/HBV co-infection: Natural course of hepatitis B Lacombe K, Rockstroh J. Gut 2012;61 (Suppl 1):i47–58 HIV-patients 3–6x more likely to develop chronic course of HBV than HIV-negative patients undergoing acute HBV infection Hepatitis B in HIV is characterized by particularly high HBV replication markers In contrast to the increased signs of HBV replication, often only mildly elevated or even normal liver enzymes

  5. Mortality of HIV/HBV co-infection pre-HAART 16 14 12 10 Liver related mortality rate/100 py 8 6 4 2 0 HBV HIV HIV/HBV Thio CL, et al. Lancet 2002;360:1921–6

  6. Treatment options for HIV/HBV

  7. Cirrhosis Yes No HBV DNA >2000 <2000 Elevated Normal ALT Therapy No Do you need to treat HBV? HBsAg+ EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

  8. CD4 >500/ulAND no indication for ART CD4 <500/ul or symptomatic HIV or cirrhosis 3TC naive 3TC experienced • Early ART including TDF + FTC or 3TC • Peg-IFN if genotype A, high ALT, low HBV DNA Monitor closely Add or substitute one NRTI with TDFas part of ART ART including TDF +3TC or FTC Current guidelines for management of HIV/HBV co-infection HIV/HBV co-infection No HBV Rx indicated HBV Rx indicated EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

  9. Liver disease associated mortality in HIV 1995–2003 GERMIVIC Rosenthal E, et al. J Viral Hepat 2007;14:183–8 ESLD associated death: % total mortality ESLD associated death: % HBsAg+

  10. Protective effect of HBV-active cART against primary HBV-infection New HBV Cases (N=35) • 1 case: woman (HBsAg negative) • 1 case: heterosexual man (HBsAg negative) • 33 cases MSM • Hepatitis (ALT 2x) 7 (20.0%) • HBsAg + 6 (17.1%) • HBeAg + 6 (17.1%) Brinkman K, et al. 20th CROI; Atlanta, GA; 2013. Abstract 33 Question:Does HBV-active cART protect against new HBV infection (HBV-PrEP)? Patient Selection: All HBV-susceptible patients at entry, anti-HBcand anti-HBs negative (<10 IU/L) and 2nd sample available in time for follow-up HBV serology All patients n=2,924, msm n=2,280, HBV susceptible + 2 samples available n=349

  11. Kaplan Meier: HBV-free survival (MSM) Log-rank P = 0.004 P< 0.001 No treatment HBV-active treatment, no TDF HBV-active treatment, with TDF Log rank P < 0.001 0 6000 Numbers in Observation No Treatment Treatment, No TDF Treatment, with TDF 107 86 189 50 67 49 19 36 38 8 16 12 Brinkman K, et al. 20th CROI; Atlanta, GA; 2013. Abstract 33

  12. 170 million people infected with HCV3–4 million new infections each year Dienstag JL, et al. N Engl J Med 2008;359:1486–500; Lavanchy D. Clin Microbiol Infect 2011;17:107–15

  13. Prevalence of HCV in the HIV population (1960/5957 patients = 33%) Regions: South Central North East North: 359 = 23.2% East: 613 = 46.9% Central: 293 = 19.6% South: 695 = 41.4% Rockstroh J, et al. J Inf Dis 2005;192:992–1002

  14. HCV co-infection in EuroSIDA Distribution of HCV by Genotype (1–4) in European Regions2 60 40 20 0 Genotype 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 Southern Europe Northern Europe Central Europe Eastern Europe 1. Rockstroh J, et al. J Infect Dis 2005;192:99–1002; 2. Soriano V, et al. J Infect Dis 2008;198:1337–1344 Prevalence of HCV seropositivity in EuroSIDA is 33%1 Of 1940 HCV Ab+ patients, 77% were serum HCV RNA-positive (95% CI: 75% to 79%)2

  15. Background 1. Rockstroh J, et al. Am J Gastroenterol 1996;91:2563–2568; 2. Graham CS, et al. Clin Infect Dis. 2001;33:562–569; 3. Weber R, et al. Arch Intern Med 2006;166:1632–41 HIV accelerates the natural course of hepatitis C1 Successful HAART can slow down fibrosis progression but not back to the rate in HCV mono-infection² Liver disease associated with HCV infection has becomea leading cause of morbidity and mortality among HIV-infected patients³

  16. Impact of ART on overall liver mortality in HIV/HCV co-infected patients Overall Mortality HAART* Cumulative survival ART No therapy *P < 0.001 0 1000 2000 3000 4000 5000 6000 Days Liver-Related Mortality HAART* ART No therapy Cumulative survival *P= 0.018 0 1000 2000 3000 4000 5000 6000 Days Bonn cohort (1990–2002) • 285 HIV/HCV co-infected patients Liver-related mortality rates per 100 person-years • HAART: 0.45 • ART: 0.69 • No therapy: 1.70 Predictors for liver-related mortality • No HAART • Low CD4 cell count • Increasing age Qurishi N, et al. Lancet 2003:362:1708–13

  17. HIV/HCV co-infectedHCV monoinfected Standardized cumulative incidenceof hepatic decompensation 0.074 0.048 P < 0.001 Hepatic decompensation risk 83% higher in the co-infected group(aHR1.83, 95% CI: 1.54 to 2.18) Lo Re V, et al. 19th IAC; Washington, DC; 2012; Abstract WEAB0102

  18. EACS guidelines: When to start Initiation of ART • ART is always recommended if CD4 count <350 cells/mm3 • Serodiscordant couples: Early ART should be considered and actively discussed • Serodiscordant couples: Early ART should be considered and actively discussed EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

  19. Median CD4-Nadir according to year of ART start and different HIV transmission groups (n=3094) Rockstroh J. Antivir Ther 2012;17:1223–5 Median CD4-Nadir 45 days prior to and up to 15 days after ART initiation (treatment was initiated ≥1996 and only inclusion of patients with treatment start after being in the cohort for at least 3 months)

  20. Current and cumulative exposure to HCV treatment Proportion N under follow-up Calendar year Mocroft A, et al. EACS Conference 2009. Abstract PS2/3

  21. Pivotal RCTs for Peg-IFN/RBV in HIV/HCV co-infection 1. Carrat F, et al. JAMA 2004;292:2839–48; 2. Laguno M, et al. Hepatology 2009;49:22–31; 3. Chung RT, et al. N Engl J Med 2004;351:451–9; 4. Torriani FJ, et al. N Engl J Med 2004;351:438–50; 5. Núñez M, et al. AIDS Res Hum Retroviruses 2007;23:972–82

  22. HCV infection can be cured Survival after HCV treatment for493 with no SVR and 218 with SVR SVR 100% No SVR 80% 60% 40% 20% P = <0.001 by log-rank test 0% 0 6 12 18 24 30 36 42 48 Months after HCV treatment Testing and counseling Treatment of chronic infection • Sustained virologicresponseis possible1 • Sustained virologicresponseis durable2 • Sustained virologicresponseprevents death3 TorrianiFJ, et al. New Engl J Med 2004;351:438–50; 2. Soriano V, et al. AntivirTher 2004;9:987–92; 3. BerenguerJ, et al. Hepatology 2009;50:407–13

  23. Proposed optimal duration of HCV therapy in HCV/HIV co-infected patients W12 W48 W72 W4 W24 24 weeks’ therapy* G2/3 HCV-RNA negative G1/4** 48 weeks’ therapy G2/3 HCV-RNA negative >2 log drop in HCV-RNA 72 weeks’ therapy G1/4 HCV-RNA positive Stop HCV-RNA positive <2 log drop in HCV-RNA *In patientswithbaselinelow viral load & minimalliverfibrosis W, week; neg, negative; pos, positive; G, genotype **Where no access to DAA available or high chances of cure even with dual therapy (favourable IL28B genotype, low HCV viral load and no advanced fibrosis) Stop EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

  24. Study 110: SVR at post-treatment week 24 (SVR24) 100 No ART EFV/TDF/FTC ATV/r/TDF/FTC Total Patients with undetectableHCV RNA (%) n/N = 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22 T/PR PR *Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient Sulkowski MS, et al. Ann Intern Med 2013 [Epub ahead of print]

  25. Interim analysis: SVR rates 12 weeks post-treatment (SVR12) 100 80 60.7* 60 SVR12 (%) 40 26.5 20 n/N = 37/61 9/34 0 BOC + P/R P/R *3 patients with missing data achieved SVR4 Interim efficacy analysis • 3 BOC patients had not yet reached SVR12 time point Mallolas J, et al. EASL 2012; Abstract 50

  26. Telaprevir + Peg-IFN + RBV in HIV/HCV co-infected patients with virologic failure on IFN + RBV: Virologic response TND UndetectableTND <LLOQ (<15 IU/mL) RVR8 EVR16 88% 88% 88% 1.5% Cotte L, et al. 20th CROI; Atlanta, GA; 2013. Abstract 36

  27. Telaprevir + Peg-IFN + RBV in HIV/HCV co-infected patients with virologic failure on IFN + RBV: Early virologic response by patient group n= 12 34 27 30 13 6 11 12 15 16 10 21 RAL F1 F2 F3 F4 RR PR NR ATVr EFV Others BrkTh Cotte L, et al. 20th CROI; Atlanta, GA; 2013. Abstract 36

  28. Grade 3–4 AEs and treatment discontinuations up to week 16

  29. BOC/IFN/RBV following virologic failure: Results by ARV regimen RVR 8 EVR 16 Pizot-Martin I, et al. 20th CROI; Atlanta, GA, 2013; Abstract 37

  30. BOC/IFN/RBV following virologic failure: Results by previous response to Peg-IFN + RBV RVR 8 EVR 16 Breakthroughn= 5 (8%) Pizot-Martin I, et al. 20th CROI; Atlanta, GA; 2013. Abstract 37

  31. Summary of key DAA and ARV DDI recommendations Telaprevir EU SmPC; Boceprevir EU SmPC; Kakuda TN, et al. IWCPHT 2012. Abstract O-18

  32. New treatment options for HIV/HCV genotype 1 patients: EACS guidelines EACS Guidelines, September 2012, Version 7.0. Available at: http://www.viraled.com/modules/info/files/files_50b4f84a4a3ac.pdf. Accessed June 2013 With first pilot studies in HIV/HCV-co-infected subjects demonstrating significant higher SVR12 rates with triple therapy compared to dual therapy HCV protease inhibitor based therapy with either boceprevir or telaprevir is now the new standard of treatment in HCV genotype 1 infection in HIV-infected individuals where available Although shorter treatment durations of triple therapy have been demonstrated to be very efficacious in HCV monoinfected subjects with rapid virological response this data so far is not available for HIV/HCV co-infected subjects

  33. Ongoing or upcoming clinical trials in HIV/HCV co-infection Boceprevir ACTG Study (RVR guided therapy) Vertex 115 (RVR guided therapy) Vertex Study in cirrhosis and HIV/HCV co-infection BI 201335 + Peg-IFN/RBV in HIV/HCV co-infected patients 1220.19 study C212 TMC-435 (RVR guided therapy) COMMAND-HIV (AI444-043) BMS790052 (RVR guided therapy) PHOTON 1 Study: GT1 HIV/HCV co-infected treatment-naïve (TN)and GT- 2/3 TN and experienced subjects with sofosbuvir + RBV 12–24 weeks AbbVie IFN-free treatment trial

  34. Management of newly diagnosed HIV/HCV co-infected genotype-1 patients Newly diagnosed chronic HCV GT 1 infection Perform Fibroscan® and/or serum marker and/or liver biopsy F0F1a F2F3a F4a In general, treatment can be deferred Consider treatment with Peg/RBV and an HCV protease inhibitor or Peg/RBV alone if low HCV viral load, IL28B CC genotype, absence of insulin resistance and high CD4 count Treatment with Peg/RBV and an HCV protease inhibitor Treatment with Peg/RBV and an HCV protease inhibitor if compensated disease Treatment should be undergone in specialised centres aMetavir fibrosis score: F0=no fibrosis; F1= portal fibrosis, no septae; F2= portal fibrosis, few septae; F3=bridging fibrosis; F4=cirrhosis; Peg, pegylated interferon; RBV, ribavirin Ingiliz P. & Rockstroh J. Liver Int 2012;32:1194–9; EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

  35. Management of HIV/HCV GT1-co-infected patients (chronic) according to prior treatment outcome Naive Relapser Nonresponder Individual decision Individual decision/triple therapy Defer F0F1 Triple therapy Triple therapy Individual decision according to disease progression F2F3 Triple therapy Triple therapy Triple therapy F4 Ingiliz P. & Rockstroh J. Liver Int 2012;32:1194–9

  36. DISCUSSION / Q&A

  37. CLOSING REMARKS Dr. Nicholas Paton Singapore

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