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

2. HIV and Hepatitis co-infection What is new? AbbVie, Symposium, Kuala Lumpur, Malaysia Jürgen K. Rockstroh Department of Internal Medicine I University Hospital Bonn Germany

3. 380 million HBV-infected subjects worldwide Dienstag JL, et al. N Engl J Med 2008;359:1486–500

4. Hepatitis delta in HIV-infected individuals 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 Total no. patients16,597 HBsAg+1,319 (7.9%) Anti-HDV Ab+ 61/422 (14.5%) (95% CI: 11.1–17.8) HDV-RNA+ 31/38 (81.6%) (95% CI: 69.3–93.9%)

5. 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

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

7. Treatment options for HIV/HBV DrugHBVHIV 3TC / FTC++ Tenofovir+++ Adefovir++? Entecavir++++ Telbivudine+++-/+ IFN / Peg-IFN++++

8. Therapy Do you need to treat HBV? 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 HBsAg+ Yes No >2000 <2000 No Elevated Normal Cirrhosis HBV DNA ALT

9. Current guidelines for management of HIV/HBV co-infection 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 HBV Rx indicated No HBV Rx indicated CD4 >500/ul AND no indication for ART CD4 <500/ul or symptomatic HIV or cirrhosis CD4 <500/ul or symptomatic HIV or cirrhosis 3TC experienced 3TC naive Early ART including TDF + FTC or 3TC Peg-IFN if genotype A, high ALT, low HBV DNA 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 TDF as part of ART ART including TDF +3TC or FTC ART including TDF +3TC or FTC HIV/HBV co-infection

10. 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+

11. Protective effect of HBV-active cART against primary HBV-infection 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-HBc and 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 1 case: woman (HBsAg negative) 1 case: heterosexual man (HBsAg negative) 33 cases MSM 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%) Hepatitis (ALT 2x) 7 (20.0%) HBsAg + 6 (17.1%) HBeAg + 6 (17.1%) New HBV Cases (N=35)

12. Log-rank P = 0.004 P < 0.001 Log rank P < 0.001 Numbers in Observation No Treatment Treatment, No TDF Treatment, with TDF 107 86 189 50 67 49 19 36 38 8 16 12 Kaplan Meier: HBV-free survival (MSM) Brinkman K, et al. 20th CROI; Atlanta, GA; 2013. Abstract 33 No treatment HBV-active treatment, no TDF HBV-active treatment, with TDF 06000

13. 170 million people infected with HCV 3 – 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

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

15. HCV co-infection in EuroSIDA 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 Distribution of HCV by Genotype (1 – 4) in European Regions 2 Northern Europe 0 20 40 60 1234 Southern Europe Central Europe Eastern Europe 123412341234 Genotype

16. 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 C 1 Successful HAART can slow down fibrosis progression but not back to the rate in HCV mono-infection² Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HIV-infected patients³

17. Impact of ART on overall liver mortality in HIV/HCV co-infected patients Qurishi N, et al. Lancet 2003:362:1708–13 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 0 1000 2000 3000 4000 5000 6000 Days Overall Mortality Cumulative survival ART HAART* No therapy *P < 0.001 Days Liver-Related Mortality Cumulative survival 0 1000 2000 3000 4000 5000 6000 HAART* ART No therapy *P = 0.018

18. Standardized cumulative incidence of hepatic decompensation Lo Re V, et al. 19th IAC; Washington, DC; 2012; Abstract WEAB0102 P < 0.001 HIV/HCV co-infected HCV monoinfected 0.074 0.048 Hepatic decompensation risk 83% higher in the co-infected group (aHR 1.83, 95% CI: 1.54 to 2.18)

19. EACS guidelines: When to start Initiation of ART –ART is always recommended if CD4 count <350 cells/mm 3 –Serodiscordant couples: Early ART should be considered and actively discussed Condition Current CD4 + lymphocyte count 350 – 500 >500 Asymptomatic HIV infectionCD Symptomatic HIV disease (CDC B or C conditions) incl. tuberculosisRR Primary HIV infectionCC Pregnancy (before third trimester)RR Conditions (likely or possibly) associated with HIV, other than CDC stage B or C disease: HIV-associated kidney diseaseRR HIV-associated neurocognitive impairmentRR Hodgkin's lymphomaRR HPV-associated cancersRR Other non-AIDS-defining cancers requiring chemo- and/or radiotherapyCC Autoimmune disease — otherwise unexplainedCC High risk for CVD (>20% estimated 10 yr risk) or history of CVDCC Chronic viral hepatitis HBV requiring anti-HBV treatmentRR HBV not requiring anti-HBV treatmentC/RD HCV for which anti-HCV treatment is being considered or givenRD HCV for which anti-HCV treatment not feasibleRC C = CONSIDER; D = DEFER; R = RECOMMENDED 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

20. 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)

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

22. 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 StudyRegimen SVR (%) G1 or G4 SVR (%) G2 or G3 Take home observations RIBAVIC 1 France (N = 412) Peg-IFN α-2b RBV 800 mg 1744 Low-dose RBV Toxicity with ddI + RBV Failure to suppress HCV RNA at week 4 <460,000 IU/mL → 100% NPV Laguno et al 2 Spain (N = 182) Peg-IFN α-2b RBV 800 – 1200 mg 2862 Weight-based RBV → higher SVR Short (24-week) therapy for genotype 2/3 not effective ACTG A5071 3 USA (N = 133) Peg-IFN α-2a RBV 600 - 1000 mg 1473 Low-dose RBV Failure to achieve week 12 EVR → 100% NPV ZDV + RBV → more anemia APRICOT 4 International (N = 868) Peg-IFN α-2a RBV 800 mg 2962 Low-dose RBV Decompensation with advanced fibrosis Genotype 1/High HCV RNA –18% SVR PRESCO 5 Spain (N = 389) Peg-IFN α-2a RBV 1000 – 1200 mg 3572 Weight-based RBV → higher SVR No increase in anemia Long (72-week) therapy not well tolerated

23. HCV infection can be cured 1. Torriani FJ, et al. New Engl J Med 2004;351:438–50; 2. Soriano V, et al. Antivir Ther 2004;9:987–92; 3. Berenguer J, et al. Hepatology 2009;50:407–13 Testing and counseling Treatment of chronic infection –Sustained virologic response is possible 1 –Sustained virologic response is durable 2 –Sustained virologic response prevents death 3 Survival after HCV treatment for 493 with no SVR and 218 with SVR Months after HCV treatment 0% 20% 40% 60% 80% 100% 0612182430364248 P = <0.001 by log-rank test No SVR SVR

24. Proposed optimal duration of HCV therapy in HCV/HIV co-infected patients 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 *In patients with baseline low viral load & minimal liver fibrosis 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) HCV-RNA negative W4W12W24W48W72 G2/3 G1/4** Stop G2/3 G1/4 24 weeks’ therapy* 48 weeks’ therapy 72 weeks’ therapy HCV-RNA positive HCV-RNA negative HCV-RNA positive >2 log drop in HCV-RNA <2 log drop in HCV-RNA

25. 100 Patients with undetectable HCV RNA (%) No ART EFV/TDF/FTC ATV/r/TDF/FTC Total n/N =5/711/1612/1528/38 T/PRPR 2/64/8 10/22 *Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient Study 110: SVR at post-treatment week 24 (SVR24) Sulkowski MS, et al. Ann Intern Med 2013 [Epub ahead of print]

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

27. Telaprevir + Peg-IFN + RBV in HIV/HCV co-infected patients with virologic failure on IFN + RBV: Virologic response Cotte L, et al. 20th CROI; Atlanta, GA; 2013. Abstract 36 TND RVR 8 EVR 16 88% 1.5% Undetectable TND <LLOQ (<15 IU/mL)

28. Telaprevir + Peg-IFN + RBV in HIV/HCV co- infected patients with virologic failure on IFN + RBV: Early virologic response by patient group Cotte L, et al. 20th CROI; Atlanta, GA; 2013. Abstract 36 n=34131210123011162761521 ATVr EFV RAL Others F1F2F3F4RR BrkTh PRNR

29. Grade 3 – 4 AEs and treatment discontinuations up to week 16 N (%), n=69 Grade 3 AEs Blood General GI Cutaneous Neurological Psychiatric Others 18 (26%) 6 (9%) 5 (7%) 2 (3%) 3 (4%) 2 (3%) 1 (1%) 2 (3%) Grade 4 AEs Blood Psychiatric 5 (7%) 4 (6%) 1 (1%) Reasons for treatment discontinuations Psychiatric AEs Cutaneous AEs Others AEs Virological failure 3 (4%) 1 (1%)

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

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

32. Summary of key DAA and ARV DDI recommendations Telaprevir EU SmPC; Boceprevir EU SmPC; Kakuda TN, et al. IWCPHT 2012. Abstract O-18 TVRBOC ATV/r Monitoring for hyperbilirubinemia recommended Consider on a case by case basis if deemed necessary DRV/r/, FPV/r LPV/r Not recommended EFVIncrease TVR to 1250 mg q8hNot recommended ETRNo dose adjustment needed RPVNo dose adjustment needed RALNo dose adjustment needed TDF Increased monitoring is warranted No dose adjustment needed

33. 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

34. 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

35. Newly diagnosed chronic HCV GT 1 infection F2F3 a 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 if compensated disease Treatment should be undergone in specialised centres a Metavir 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 Management of newly diagnosed HIV/HCV co-infected genotype-1 patients 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 Perform Fibroscan® and/or serum marker and/or liver biopsy F0F1 a F4 a Treatment with Peg/RBV and an HCV protease inhibitor

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

39. DISCUSSION / Q&A

40. CLOSING REMARKS Dr. Nicholas Paton Singapore