1. HCV and HBV co-infections Sanjay Bhagani Royal Free Hospital London EACS Advanced Course 2008

3. Causes of Liver Disease in HIV Infection

4. Mortality of HIV-infected patients in France (GERMIVIC Study Group) Rosenthal et al. AASLD 2004; Abstract 572.

5. 40 million 175 million HIV HCV Overlapping HCV & HIV Epidemics 10 million 25% of HIV

6. Significant increase in new acute HCV infections amongst HIV+MSM since 2001 Test for trend p-value using Poisson regression p<0.001 Error bars = 95% CI Incidence of acute HCV infection/1000 pt yrs 0 5 10 15 20 25 30 1997199819992000200120022003 Browne RE, et al. 2nd IAS 2003; Abstract 972

7. Reports of acute HCV in HIV+ MSM across Europe Danta et al. AIDS 2007; 21: 983-991. Gambotti et al. Euro Surveill 2005; 10: 115-117. Ghosn et al. Sex Transm Infect 2006; 82: 458-460 ; 40: 41-46. Serpaggi et al. AIDS 2006; 20: 233-240.Vogel M et al. J Viral Hepat 2005; 12: 207-211

8. Risk Factors for Acute HCV in MSM Group Sex Sexual practice Drug practice High-risk practices Internet Shared implements Club drugs STI Danta et al, AIDS 2007

9. Phylogenetic Tree Constructed from Analysis of Paired Samples (red) Compared with Genebank Samples (black) Jones et al. CROI 2008;Oral Abstract 64LB. Is HCV Viraemia after SVR Following Initial Infection Re-infection or Relapse?

10. Effect of HIV/HCV co-infection on hepatic fibrosis progression Effect of HIV/HCV co-infection on hepatic fibrosis progression ( Benhamou et al 1999 ) Fibrosis progression influenced by CD4 cell count (< 200 cells/microlitre) Age at infection ( > 25 years) Male sex Alcohol consumption ( > 50g/d) Fibrosis grade

11. HIV-HCV Alcohol HBV Haemochromatosis HCV Steatosis BMI>25 2PBC 0.00 0.17 0.33 0.50 0.67 0.83 1.00 020406080 Hazard function 4682 patients Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265 Age in years Progression to cirrhosis

12. HIV/HCV - Cirrhosis and survival Pineda et al. Hepatology 2005

13. A) Overall-Mortality Observation time[days]] 500040003000200010000 Cumulative survival 1,1,9,7,5,3 P<0.0001 Patients with HAART Patients with ART untreated Patients 6000 Patients under observation: HAART-group:937933--- ART-group:5546301591 Untreated-group: 1379449373227 6000500040003000200010000 1,1,9,7,5,3 B) Liver-related-Mortality P<0.018 Patients with HAART Patients with ART untreated Patients Overall and Liver-related Mortality - effect of HAART Qurishi N et al. Lancet, 2004 Cumulative survival Observation time[days]] Patients under observation: HAART-group:937933--- ART-group:5546301591 Untreated-group: 1379449373227

14. % LEE by co-infection status 1.Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88 Interactions were not significant between drug CLASS and CO (p=0.800) N arms 11 7 4 12 9 3 14 10 4 11 6 5 5 3 2 53 35 18 N patients 581 1242 2705 2038 1055 7621 244 737 2321 630 572 4504 337 505 384 1408 483 3117 0 10 20 30 40 NNRTIPIMixedBPINRTIOverall Drug Class % Patients with LEE All PatientsHCV Co-infHIV Only

16. Treating HCV in HIV- infected patients HAART treated HIV patients live longer Faster progression to liver cirrhosis Increased mortality due to end stage liver disease Higher risk of hepatotoxicity following treatment with ART drugs Risk of hepatotoxicity reduced with successful HCV erradication

17. Response to PegIFN and Ribavirin in HIV/HCV co-infected patients

18. Acute HCV/HIV: Overall virological responses: 133 = 56 89 95 99 85 3 rd Int HIV/Hepatitis co-infection meeting, Paris 2007

19. APRICOT – Peg IFN 2a + Ribavirin arm SVR by genotype and viral load High > 800 000 iu/l Low < 800 000 iu/l Torriani et al, NEJM 2004

20. Predictors of response Host Acute infection Younger age Lack of stage 3/4 fibrosis Ethnicity Low BMI Lack of hepatic steatosis High CD4 % Lack of insulin resistance Virus Genotypes 2/3 Low viral loads

21. Gt 1 (n = 150) 34 16 27 29 Gt 2/3 (n = 78) 47 73 62 69 APRICOT: Baseline CD4+ Count and Efficacy of Peg-IFN alpha-2a Plus RBV Retrospective analysis of HIV/HCV-coinfected patients treated with peg-IFN alpha-2a + RBV in APRICOT SVR rates analyzed in overall population and within genotypes according to baseline CD4+ cell count quartiles (Q1-Q4) Rate of SVR varied according to CD4+ cell percentage quartile in genotype 1 but not in genotypes 2/3 Dieterich D, et al. ICAAC 2006. Abstract H-1888. 0 20 40 60 80 100 Pts With SVR (%) Q4 (32.1% to 69.3%) Q1 (2.5% to 19%) Q2 (19.1% to 25.0%) Q3 (25.0% to 32.1%)

22. APRICOT: SVR rates according to exposure Genotype 1 recipients of peginterferon alfa-2a plus ribavirin 39% SVR rate (%) 80/80/80 exposure 0 10 20 30 40 50 11% <80/80/80 exposure* 62 29% All patients n = 176 114 *Patients violated the rule if 1 of the three targets were not achieved Opravil M, et al. 45th ICAAC 2005; Abstract 2038

23. Why lower response rates to anti-HCV therapy in HIV+ patients? Use of lower doses of RBV in most trials More advanced fibrosis grade Higher rate of steatosis (NRTIs, PIs) Unfavourable baseline HCV virological features Higher discontinuation due to side effects Lower initial HCV-RNA clearance Higher relapse rates

24. Viral Dynamic response to interferon and ribavirin Pawlotsky Hepatology 2002; 32(4)

25. Does RVR predict response? (week 4 undetectable HCV RNA) APRICOT –PPV 82% –NPV 79% RIBAVIC –PPV 97.5% –NPV 81.3% PRESCO –Lack of RVR independent predictor of relapse Crespo M et al. –G3 patients with RVR low rates of relapse with 24 weeks of therapy ROMANCE –G2/3 patients without RVR need longer Rx (48 weeks)

27. How can we maximise response to therapy?

28. Zidovudine: impact on HCV treatment Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

29. Interactions between RBV & nucleoside analogues AZT ddI d4T anemia hepatic pancreatitis weight decomp. & lactic acidosis loss mitochondrial DNA synthesis lactate Blanco et al. NEJM 2002; 347: 1287

30. Abacavir and SVR Vispo et al, 3 rd Int. HIV/hepatitis Conference, Paris 2007. Abs 46

31. V. Soriano. http://www.medscape.com/viewarticle/561043_1

32. Dose of Ribavirin?

33. Study Design n=389 Study weeks 0 96 72 48 24 60 84 Peg-IFN + RBV 1000-1200 mg/day 12 36 Follow-up G2,3 G1,4 G2,3 Follow-up Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment. N=192 N=45 N=96 N=56 PRESCO

34. Overall Results No. 67.3% 55% 90.1% 41% 262 106 137 1919 TotalG1G2/3 389191152 49.6% 35.6% 72.4% 32.6% 193 68 110 1515 G4 46 Sustained virological response End of therapy PRESCO p<0.00001

35. Importance of weight-based Ribavirin (1000mg 75kg) Soriano, et al. AIDS 2007. 21: 1073-89

36. Extended duration of therapy?

37. Utilising kinetics to determine length of therapy – mathematical model Genotype 1 End Rx HCV RNA 36 weeks < 50 c/ml Drusano & Preston. JID 2004; 189: 964-970

38. Retrospective analysis of genotype 1 patients receiving 48 weeks of pegIFN alfa-2a + RBV (N = 453) Longer Duration of Undetectability on Treatment Increases Chance for SVR HCV RNA Positive at Week 24 41224 Week Became HCV RNA Negative 91 66 45 2 Ferenci P, et al. J Hepatol. 2005;43:425-433. 20 40 60 80 100 SVR (%) 0

39. Treatment of Chronic HCV Extending Therapy 61 52 32 45 0 20 40 60 80 4872 Weeks of Treatment % HCV RNA (-) EOT SVR Extending the duration of therapy reduced relapse from 47% to 13% Sanchez-Tapias et al. AASLD 2004. Abstract 126.

40. Results (On Treatment analysis) 56 15 (8%) 36 (80%) 9 (16%) Voluntary withdrawals (64) 4 (4%) Short arm Extended arm PRESCO 192 4596 No. of patients (389) 31% 53% 67% 82% G 1/4 G 2/3 59 24 46 64 p=0.004 p=0.04

42. Untreated Follow-up SLAM-C trial in HIV–HCV co-infected non-responders (Sherman) Peg-IFNα-2a 180 µg plus RBV 800–1200 mg HCV RNA 2 log drop NR and naïve n=200 HCV RNA <2 log drop 12 weeks Peg-IFNα-2a 180 µg plus RBV 800–1200 mg Peg-IFNα-2a 180 µg Stop treatment, observation period 60 weeks 72 weeks 24 weeks Randomisation

43. Maintenance IFN for HCV HALT-C Final Results Low dose peginterferon alfa-2a arm (90 µ g/week) vs control group had –Greater reductions in HCV RNA and ALT (P <.0001) –Greater reductions in necroinflammation (P <.001) No reduction in fibrosis or difference between arms No significant difference between arms in any primary outcome –34.1% vs 33.8%: HR 1.01 (95% CI, 0.81-1.26) Di Bisceglie A, et al. AASLD 2007. Abstract LB1. Study ArmBaseline Fibrosis* Any primary outcome, % Death, % HCC, %CTP score 7, % Peginterferon alfa-2a 90 µg/week (n = 517) 3/436.62.6 3.2 5/630.12.41.917.8 Control (n = 533) 3/435.50.61.63.2 5/631.12.74.614.6 *Ishak Score

45. Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000. New oral small molecule ARVs in development for the treatment of HCV Drug nameDrug classPreclinicalPhase IPhase IIPhase III MK-0608 (Merck) R7128 (Pharmasset & Roche) NIM811 (Novartis) ITMN-191 (InterMune & Roche) MK-7009 (Merck) BI12202 (Boehringer) R1626 (Roche) DEBIO-025 (Debiopharm) BI 1220 (Boehringer) Telaprevir (Vertex Pharmaceuticals) Boceprevir (Schering-Plough) TMC435350 (Tibotec & Medivir) Nucleoside polymerase inhibitor Cyclophilin inhibitor Protease inhibitor Nucleoside polymerase inhibitor Cyclophilin inhibitor Nucleosite polymerase inhibitor Protease inhibitor X X X X X X X X X X X X X

46. TELAPREVIR: PROVE 2 SVR 2) S26 1.Dusheiko et al.Treatment of chronic hepatitis C with telaprevir in combination with peginterferon alfa 2a with or without ribavirin: further interim analysis results of the PROVE2 study. J Hepatology 2008; 48 (suppl)

47. Take home messages: HIV/HCV co-infection is common Increasing incidence of acute HCV ESLD major cause of morbidity/mortality Early HAART beneficial –Avoid d-thymidine analogues/AZT Treat HCV with PegIFN and Ribavirin –Best results if HCV treated in the acute phase –Maximal doses of Ribavirin (1000/1200mg) –Avoid AZT, d4T and DDI, –?Avoid Abcavir –EPO and G-CSF – avoid dose reductions

48. Take home messages: Duration of therapy individualised –Genotype –Pre-Rx viral load –Fibrosis stage –RVR/EVR No role for maintenance low-dose IFN Give some thought to hepatic steatosis New anti-HCV drugs (STAT-Cs!) will be available in the future… …be careful out there….!!!

49. Proposed optimal duration of HCV therapy in HCV/HIV-coinfected patients. W4 W12 W24 W48W72 HCV-RNA neg HCV-RNA pos > 2 log drop in HCV-RNA < 2 log drop in HCV-RNA HCV-RNA neg HCV-RNA pos G2/3 G1/4 Stop G2/3 G1/4 24 weeks therapy * 48 weeks therapy 72 weeks therapy * In patients with baseline low viral load and minimal liver fibrosis. EACS Guidelines 2008

50. 40 million 400 million HIV HBV HBsAg+ Overlapping HBV & HIV Epidemics 4 million 5–15% of HIV

51. HBsAg Prevalence 8% – High 2–7% – Intermediate <2% – Low Geographic Distribution of Chronic HBV Infection

52. Hepatitis B Disease Progression Acute Infection Chronic Infection Cirrhosis Death 1. Torresi, J, Locarnini, S. Gastroenterology. 2000. 2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995. 3. Moyer, LA, Mast, EE. Am J Prev Med. 1994. 4. Perrillo, R, et al. Hepatology. 2001. 5%-10% of chronic HBV- infected individuals 1 Liver Failure (Decompensation) 30% of chronic HBV- infected individuals 1 >90% of infected children progress to chronic disease <5% of infected immunocompetent adults progress to chronic disease 1 23% of patients decompensate within 5 years of developing cirrhosis 3 Liver Cancer (HCC) Chronic HBV is the 6th leading cause of liver transplantation in the US 4 Liver Transplantation Clearance

53. Phases of chronic HBV Infection Immune tolerant phase –High levels of HBV DNA –Very little inflammation Chronic hepatitis –HBeAg positive High levels HBV DNA, inflammation/progressive fibrosis –HBeAg negative Low levels HBV DNA, progressive inflammation and fibrosis Inactive HbsAg carrier state (non replicative phase) –HBeAg negative, low/absent HBV DNA, no inflammation/fibrosis

54. Emergence of the e-negative Precore Mutant HBeAg+ HBV-DNA (mutant) HBeAg / anti-HBeAnti-HBe+ HBV-DNA (wild) Transaminases Chronic hepatitis mild Chronic moderate to severe hepatitis Cirrhosis & hepato- cellular carcinoma HBV tolerance HBV wild-type clearance Continued HBV precore mutant replication 05101520 Years Carman WF et al Viral Hepatitis. Scientific Basis and Clinical Management. NY: Churchill Livingstone; 1993:121.

56. Geographical distribution of HBV genotypes A to H North Europe & USA - A Mediterranean basin- D Africa E & D India A A Rare types: F – Latin America G –France, USA H –Mexico, Latin America Far East B & C

58. Hepatitis B Serology Isolated HBcAb+ HIV negative – 50% true positive HBcAb – <2% with detectable serum HBV DNA HIV positive – 60-90% true positive HepBcAb – Many with detectable HBV DNA (~15% at RFH) – ~40% with necro-inflammation on liver biopsy Isolated anti-HBc more common in HIV/HCV Implications for 3TC based HAART and vaccination strategies Hofer, Euro J Clinical Micro 1998. Ghandi, CID. June 15, 2003. Nebya, BHIVA 2006

59. HIV/HBV Coinfection Increased incidence of chronic HBV in HIV+ patients (Lazizi JID 1988). Will vary greatly with subpopulation HIV+ pts 3-6x more likely to develop chronic HBV than HIV- (Bodsworth JID 1991) HBeAg and HBV DNA higher levels in HIV+ but AST/ALT lower (Perillo 1986) Increased hepatic fibrosis Decreased spontaneous seroconversion (Krogsgaard 1987) or seroreversion of prior HBV infection with loss of anti-HBs and return of HBsAG (Waite AIDS 1988) Atypical serologies: anti-HBc may indicate chronic infection (Hofer 1998)

60. Liver Mortality Rate (per 1000 PY) MACS Thio et al. Lancet 2004

61. * Adjusted for age, sex, cigarette smoking, and alcohol consumption. 300 - < 10 4 10 4 - 10 5 HBV DNA copies/mL 10 5 - 10 6 All Participants (n = 3582) * RR * (95% CI) *P <.001 6.5 5.6 2.5 1.4 0 2 4 6 8 10 12 14 > 10 6 * * HBeAg(-), Normal ALT (n = 2923) 300 - < 10 4 10 4 - 10 5 > 10 6 HBV DNA copies/mL 10 5 - 10 6 6.6 5.6 2.5 1.4 *P <.001 * * * 0 2 4 6 8 10 12 14 Level of HBV DNA (PCR-assays) at entry & progression to cirrhosis in population-based cohort studies 3582 HBsAg untreated asian carriers mean follow-up 11 yrs 365 patients newly diagnosed with cirrhosis Iloeje UH, Gastroenterology 2006; 130: 678-686 HBV-DNA viral load (> 10 4 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg status

62. HBV-DNA levels (> 10 4 cp/ml) strong predictor of HCC, independent of HBeAg, ALT and cirrhosis Entire cohort (N = 3653) HBV-DNA (cp/ml)RR < 300 1.0-9.9 x 10 4 1.0-9.9 x 10 5 > 1.0 x 10 6 1.0 2.3 6.6 6.1 Subcohort (N = 2925) HBV-DNA (cp/ml)RR < 300 1.0-9.9 x 10 4 1.0-9.9 x 10 5 > 1.0 x 10 6 1.0 4.5 11.3 17.7 Population based cohort study of HBsAg asian carriers, mean follow-up= 11.4 Chen CJ et al JAMA 2006;295:65-73 13.5 % 7.9 % 0.9 % 0.7 % 3.1 % >6log 5-6log 4-5log <4log Level of HBV DNA (PCR-assays) at entry & risk of HCC HBeAg ( ), Normal ALT, No cirrhosis at entry (n = 2925) >6log 5-6log 4-5log <4log 14.9% 12.1% 3.5% 1.3% Entire cohort (n = 3653)

63. How? Restoring immune control Type I interferons –Interferon-alpha –Pegylated interferon- alpha-2a ?others Viral replication suppression with antivirals Lamivudine Adefovir Entecavir (Tenofovir) (FTC) Telbivudine (Clevudine)

64. Author(Yr.)n. Tx n. Controls Hoofnagle(88)10 4 Brook (89)16 6 Brook (89) 6 9 Pol (92)1614 Wong (95)1313 All 6146 100 100 0,10,01 8,9 16 RCT IFN- vs placebo 837 HBsAg+ - 107 HIV+ included in 5 studies HBe seroconversion/negativation : HIV+ vs HIV: – 0.38 (CI 0.06-0.7 P =.02) IFN- in HBV /HIV co-infection IFN Placebo Puoti et al. personnal comm.

65. Serum HBV DNA Dore GJ, et al. J Infect Dis. 1999;180:607-613. HIV/HBV Lamivudine -2.7 log 10 copies/mL

66. HBV DNA (log 10 copies/ml) - 6.2 log 10 c/ml p<0.001* ADV (weeks) - 5.9 log 10 c/ml p<0.001* - 4.7 log 10 c/ml P<0.001* - 5.5 log 10 c/ml p<0.001* 3129 31 30 312927 n = 35 27 patients remain on study * p<0.001 Wilcoxon Sign Rank Test Benhamou et al. Lancet. 2001;358: 718-23. & J Hepatol. 2006;44:62-7. HBV DNA (< 2.6 log 10 copies/ml) 8/35 HBeAg negative3/33* HBe seroconversion 2/33* HIV/HBV LAM-R ADV

67. Tenofovir for HBV - Gilead Study 903 HIV/HBV Coinfected Patients Mean Change from Baseline in HBV DNA (95% CI) TDF+LAM+EFV: 5 d4T+LAM+EFV: 6 5 6 5 6 4 5 5 6 Change From Baseline in log 10 HBV-DNA (copies/mL) -8 -7 -6 -5 -4 -3 -2 0 Weeks BL12243648 -2.95 -4.70 TDF+LAM+EFV d4T+LAM+EFV Cooper D. 10th CROI, Boston MA, February 10-14, 2003, Abstract # 825

69. Similar (better?) Anti-HBV Activity of Tenofovir compared to Adefovir in Coinfected Patients Interim data from ACTG A5127: HBV/HIV-1 coinfected pts –HBV DNA 100,000 –Stable antiretroviral therapy; HIV-1 RNA 10,000 Reduction in HBV DNA with tenofovir noninferior to adefovir Peters M, et al. CROI 2006 Abstract 124. HBV DNA (log 10 ) 0 2 4 6 8 10 020406080 90 Weeks 48 Adefovir Tenofovir DF

70. GLOBE: Year 1 Results of Telbivudine (LdT) for Chronic Hepatitis B Lai et al. AASLD;2005. Abstract LB01. Summary of Year 1 Results With Telbivudine OutcomeHBeAg-Positive PatientsHBeAg-Negative Patients LdT, % (n = 458) LAM, % (n = 463) LdT, % (n = 222) LAM, % (n = 224) Undetectable HBV DNA Week 52 Week 76 75* 75* (n = 163) 67 58 (n = 165) 88* 84* (n = 68) 71 67 (n = 67) Virologic breakthrough by Week 48 3*102*9 Normalized ALT Week 52 Week 76 77 78* (n = 163) 75 68 (n = 165) 74 76 (n = 68) 79 64 (n = 67) Fibrosis decline by Wk 5268615946 HBeAg seroconversion by Week 76 41* (n = 100)26 (n = 93)N/A *P <.05 vs lamivudine.

71. Potent Anti-HBV Activity From Addition of Entecavir to Continued 3TC in Coinfection ETV-038: HBV/HIV coinfected pts –HBV DNA 100,000, HBeAg+ or -, HBsAg+, compensated –HIV RNA < 400 for 12 weeks –3TC-containing HAART for 24 weeks or YMDD mutation, no other agent with anti-HBV activity Entecavir (1 mg QD) vs placebo added to continued 3TC for 24 wks 84% ETV had HBV DNA < 400 or 2 log reduction by Week 24 No difference in AEs RT sequencing for mutations M204V/I, L180M (3TC mutations) and T184, S202 and M259 (ETV mutations) at baseline and at week 48 Pessoa W, et al. CROI 2005, Abstract 123, Colonno et al, CROI 2006, Abstract 832 51 17 46 16 48 16n = 49 16 *P <.0001 -3.66 -5 -4 -3 -2 0 1 021224 +0.11 * * * Weeks Placebo Entecavir Mean HBV DNA by PCR (log 10 )

72. % Patients Clinical lamivudine resistance (phenotypic resistance) 1 Detection of lamivudine-resistant mutations (genotypic resistance) 2 3 45 years Adefovir-resistance (van Bömmel F, Mihm U, Jung C, Berg T. AASLD 2003 Locarnini S et al EASL 2005, Abstract 36) (Hadziyannis S et al. AASLD 2005 Abstract LB14) Resistance development – Nucleos(t)ides

73. Comparative Incidence of HBV Resistance in Patients Treated with ADV or LAM 1. Benhamou Y. et al., Lancet (2001) 358:718-723 2. Qi, et al., EASL 2004, Apr 16, 2004, Berlin 3. Lai C.L., et al., Clinical Infectious Diseases (2003) 36:687 4. Benhamou Y et al. Hepatology 1999; 30:1302-6 * Year 4 resistance rate for ADV not yet available Incidence of Resistance ADV 1,2,* (N236T or A181V) LAM 3 (YMDD ) LAM 4 (YMDD in HIV/HBV) 0% 24% 2% 42% 47% 3.9% 53% 70% 90% 0% 20% 40% 60% 80% 100% year 1 year 2year 3year 4

74. Resistance Mutations Associated with Viral Breakthrough in Patients on Treatment Locarnini S et al. Antivir Ther 2004;9:679–93. V214A/Q215S V84M/S85A A181V/T M250V L180M T184G/S S202I N236T M204/I LAM ADV ETV LdT FTC Selection of LAM-Resistant Mutants Affects Future Treatment Options

75. Envelope changes Polymerase changesAg–Ab binding [IC 50 (μg/ml)] Wild type 1.09 HBIG escape sG145R Anti-viral drug resistant sE164D sW196S sI195M sM198I sE164D/I195M rtW153G rtV173L rtM204I rtM204V rtV207I rtV173/rtL180/rtM204V >55.0 14.86 8.29 5.26 12.5 54.53 Cooley L et al. AIDS 2003;17:1649–57. Envelope/Polymerase Mutations and the Antigen/Antibody Binding Capacity in Genotype A and D HBV/HIV Co-infected Subjects (n=9) with LAM Resistance

76. Anti-HIV activity of entecavir 17 HIV/HBV coinfected pts (10 naïve, 7 treatment-experienced from US and Australia) who received entecavir (ETV) monotherapy for HBV therapy. ETV monotherapy results in clinically-significant reduction in plasma HIV-RNA in the majority but not all pts, and can select for the M184V mutation even in naive pts HIV/HBV co-infected individuals should not receive ETV monotherapy Selection of M184V following ETV tx 0 10 20 30 40 50 60 70 ART naïve Total Median time to M184V 148 days 98 days % with M184V 3/7 3/5 6/12 ART experienced Risk factorp value Total duration on ETV0.05 Magnitude of HBV-DNA reduction on ETV 0.04 HIV-RNA pre-ETV therapy0.87 HBV-DNA pre-ETV therapy0.69 Nadir CD4+ count0.20 1. Audsley J, et al. 15th CROI, Boston 2008, No.63 Univariate analysis for selection of M184V

77. Conclusion: TDF/3TC superior to 3TC alone but not TDF in HBV naïve No benefit continuing 3TC in experienced HBV viraemic patients No difference between adding or switching TDF TDF vs TDF/3TC vs 3TC in drug-naïve HIV/HBV coinfected 3TC - Naive P=0.045 vs. 3TC N = 10 116 1. Nelson M, et al. A 48 week study of tenofovir or lamivudine or a combination of tenofovir and lamivudine for the treatment of chronic hepatitis B in HIV/HBV co-infected individuals. 13th CROI. Denver, CO, February 5-8, 2006; Abst. 831. -6 -5 -4 -3 -2 0 BL 24 weeks TDF3TCTDF/3TC

78. LdT FTC Anti HBV Drugs in HIV Infection TDF ADF ETV ETV in LAM exp LAM Genetic Barrier Potency No anti-HIV activity Anti-HIV activity IFN Cumulative toxicity with ART (AZT, ddI) 1 Log HIVRNA 1 Log HIVRNA CD4 counts = % CD4 counts = % Partial Anti-HIV Activity M184V accumulation

79. Treatment Algorithm: Patients with Compensated Liver Disease and No indication for HIV therapy (CD4 count > 350/µl) No treatment Monitor every 6–12 months Monitor ALT every 3- 12 months Consider biopsy and treat if disease present*** PEG IFN**** (favorable response factors are: HBeAg+ - HBV Genotype A – elevated ALT and low HBV-DNA) Telbivudine (if HBV-DNA ist still detectable at week 24 add adefovir to minimize resistance development risk) Adefovor and telbivudine de novo therapy Early HAART initiation including Tenofovir+3TC/FTC ALT Elevated ALT Normal HBV DNA 2,000 IU/mL HBV DNA <2,000 IU/mL** HIV/HBV* Soriano V, et al. 4 th IAS, Sydney 2007, #MoBS104; Benhamou Y, 3rd International Workshop on HIV and hepatitis coinfection, Paris 2007

80. Immediate indication for HIV treatment HBV-DNA > 2000 IU/ml HBV-DNA < 2000 IU/ml HAART including TDF + 3TC or FTC Substitute one NRTI by Tenofovir or add Tenofovir* Patients without HBV associated 3TC resistance Patients with cirrhosis ECC Statement J Hepatol 2005 Patients with HBV associated 3TC resistance HAART regimen of choice HAART including TDF + 3TC or FTC Management and therapeutic options in HIV-HBV co-infected patients with an indication of anti-HIV therapy *if feasible and appropriate from the perspective of maintaining HIV suppression Refer patient for liver transplantation evaluation if liver decompensation occurs