1. Hep B and C: Updates and Resources John Scott, MD, MSc Asilomar AETC Conference October 6, 2006

2. Outline Hepatitis C –Background & natural history –Treatment of Hep C/HIV coinfection New drugs Guidelines and Internet resources Hepatitis B –Natural history w/ and w/o HIV –Treatment of Hep B monoinfection –Treatment of Hep B/HIV coinfection New drugs Guidelines and Internet resources

3. Biology ss RNA virus RNA-dependent RNA polymerase, lacks proofreading function Flaviviridae 6 genotypes, type 1 accounts for 70% of infections in US, types 2,3 account for rest No easy culture system! www.hepcprimer.com/3dmodel.html

10. Liver Disease has Emerged as a Major Cause of Death in the HAART Era Bica Clin Infect Dis 2001; Puoti JAIDS 2000; Soriano Eur J Epidemiol 1999; Soriano PRN Notebook 2002; Martin-Carbonero AIDS Res Human Retrovirus 2001 0 10 20 30 40 50 60 Mortality (%) Death from end-stage liver disease (ESLD) as a % of all deaths among HIV patients Italy (Brescia)Spain (Madrid)USA (Boston) 13% 35% 5% 12% 45% 50% Pre-HAART era HAART era

11. Impact of HIV on HCV Cirrhosis Decompensation Makris Soto Pol Benhamou Combined 0.761.02.0710.83 Eyster Telfer Makris Lesens Combined 0.611.06.14175.32 Graham CID 2001 Relative Risk (95% CI) AB

12. AASLD Guidelines Anti-HCV testing on all HIV+ pts HCV RNA to confirm Ab+ and all Ab- w/ unexplained liver disease Treat HIV/HCV patients in whom likelihood of serious liver dz and tx response outweigh the side effects of tx PegIFN-alfa + ribavirin x 48 wks Closely monitor pts on therapy Use RVN carefully in pts on AZT or d4T. Avoid RVN and ddI Decompensated liver dz -> liver transplant eval Strader D. Hepatology 2004.

13. Workup H&P: date HCV diagnosed, risk factors, earliest exposure, signs and symptoms of hepatitis and cirrhosis, alcohol hx, prior treatment and response Candidate for tx: depression, poorly controlled DM, CAD, cytopenias, autoimmune dz, pregnant EIA (TPR>99%, TNR=99%) If EIA+, sensitive PCR assay LFTs, CBC, chem 7, TSH, hepatitis serologies, CD4 and HIV RNA, pregnancy test, eye exam, utox? If treatment contemplated, then HCV genotype and viral load, +/- liver biopsy

14. Liver Biopsy Currently the best way to determine how much scarring is present, but imperfect Needle, local anesthetic Risks: bleeding Scar Stages: 0-1-2-3-4 (Batts-Ludwig) VA guidelines recommend bx for all patients

15. Progression of Fibrosis on Biopsy No Fibrosis Stage 1: Fibrous expansion of some portal areas Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 4: Cirrhosis Cirrhotic liver: Gross anatomy of cadaver Courtesy of Gregory Everson, MD.

16. ACTG 5071 (Chung RT, NEJM 2004; 351:451-9) RIBAVIC (Carrat F, JAMA 2004; 292:2839-48) APRICOT (Torriani F, NEJM 2004: 351:438-50) –All compared standard with pegylated IFN –All treated for 48 weeks, regardless of genotype –All used low-dose RBV (avg dose 800 mg/d) Laguno et al (AIDS 2004: 18:27-36). –Higher dose RBV, 24 weeks for GT2 or 3 Prospective, Randomized Multicenter Trials of Pegylated Interferons in HIV/HCV

17. HIV/HCV Coinfection Trials ACTGRIBAVICAPRICOTLaguno # pts13441286095 % genotype 178%66%61%49% fibrosis score2.52.316% cirrhotic30% st 3 or 4 Mean CD4475515530560 Overall SVR27%26%40%44% SVR GT 15%15%29%38% SVR non-130%43%62%53% d/c rate (ea arm)12%42%30-40%17%

18. Side Effects of PegIFN/Ribavirin Depression ranging from mild to suicidality Irritability, aggressive behavior Worsening of mania Fatigue Insomnia Myalgias, fever, flu- like symptoms Hair loss Cytopenias “Interferon Man”

20. High relapse rate (33-44%) in HIV/HCV Torriani, F. 2004 NEJM 351:438-51 Soriano, V. 2004 AIDS Research Human Retrovirus 20:351-3.

21. Extended treatment for HCV Mathematical models show that viral suppression necessary for at least 36 weeks HCV monoinfected trial showed that if HCV RNA + at wk 12 but – at wk 24, SVR increased from 17% to 29% with add’l 24 weeks of therapy Goal: reduce relapse rate Drusano GL. 2004 J Infect Dis 189:964-70 Berg T. 2006 Gastro 130:1086-97.

22. Duration of Detectability (DUD) 4 12 24 48 Time (weeks) RVR EVR Slow VR Detectable Undetectable 44 wks 36 wks 24 wks Ferenci 2005, Fried 2006

23. PRESCO Ongoing Spanish study of 398 stable coinfected pts (mean CD4 562 cells/mm 3 ) All are receiving 180 mcg PegIFNα2a (Pegasys) and wt-based RBV (1000 or 1200 mg/d) Comparing extended tx w/ std tx: –48 weeks for GT non-1 –72 weeks for GT 1 Soriano, et. al., 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) October 30 - November 2, 2004, Washington, DC (abstract)

25. % HCV Responders at Week 4 GenotypeStudy# patientsHCV-RNA reduction > 1 log 10 HCV-RNA reduction > 2 log 10 Serum HCV-RNA- negative Genotype 1 PRESCO9469.246.233.8 Fried29878.855.331.2 APRICOT176684013 Genotype 3 PRESCO7093.889.685.4 Fried1409590.784.2 APRICOT96878037 Soriano V. 2 nd Intl Workshop on HIV and HCV 2006

26. PRESCO: Interim Analysis End-of-treatment results for 181 pts: –Overall, 63% response rate –50% for GT 1 –85% for GT 2/3 Highest response rates reported so far for coinfected pts.

27. HRN-004SLAM-CENDURE Patient populationNonresponse F > 0/CPT < 6 Any F > 0/CPT < 6 Any CPT ≤ 8 Number of patients100300468 EndpointHistology/clinic al Clinical Arm 1PEG-IFN alfa 2a 90 mcg PEG-IFN alfa- 2a 180 mcg PEG-IFN alfa 2b 0.5 mcg/kg Arm 2Observation Treatment duration (years) 1.5 Recruitment statusCompleteEnrollingLaunch 2006 2nd Intl Workshop on HIV and HCV 2006 Maintenance Therapy Trials for Prior Non-responders

28. Drugs in development Serine protease inhibitors Polymerase inhibitors Helicase inhibitors Antisense therapy siRNA Toll-like receptor agonists Therapeutic vaccination Cyclosporine analog Improved Ribavirin and Interferon Review: McHutchison JG. 2006 J Hepatol 44:411-21 Source: www.clinicalcareoptions

29. Hepatitis B: Epidemiology HBV very common worldwide, ~350 million infected 1.25 million Americans chronically infected 70,000 new cases annually in US HBV is 10x more common in HIV+ than in general population Highest rates among HIV+ seen in MSM (6-10%) Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006. Nunez M, et al. Lancet Infect Dis 2005.

30. Clinical-Epidemiologic Correlations HBV Endemicity Location Age of Infection Mode of Transmission Chronicity HCC Risk High 10-15% Asia Sub-Sahara Africa Birth Toddler Perinatal Horizontal LikelyHigh Low < 2% N. America W. Europe Scandinavia Early Adulthood Percutaneous Sexual RareLow Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed February 6, 2006.http://www.who.int/mediacentre/factsheets/fs204/en/ Designed by Jules Dienstag, MD clinicaloptions.com/hep

31. Prevalence of Chronic Hepatitis B HBsAg Prevalence > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from 1996-2002 ~ 2 million Asians ~ 400,000 South Americans ~ 350,000 Africans ~ 930, 000 Europeans Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2006. clinicaloptions.com/hep

32. Natural History of Chronic HBV Infection 0 10 20 30 40 50 60 70 Years Serology HBeAgAnti-HBe ALT level HBV DNA level (viremia) Disease Chronic active hepatitis Cirrhosis/HCC Immune tolerant (phase I) Immune Active (phase II) Non-Replicative (phase III) Chronicity Stage Minimal inflammation Resolved Normal to cirrhosis/HCC HBsAgAnti-HBs clinicaloptions.com/hep

33. Outcomes of Acute HBV Infection Recover Subclinical Hepatitis Fulminant Hepatitis Acute Hepatitis ACUTE INFECTION Chronic Infection DEATH < 1% 0.1-2.7% 5-20% Risk is Related to Age at Infection OutcomeNeonates, %Children, %Adults, % Chronic carrier9020< 5 Recover1080> 95 Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. clinicaloptions.com/hep

34. Possible Outcomes of HBeAg+ Chronic HBV Infection Patient Populations in Chronic Hepatitis B Marker Immune Tolerant HBeAg+ CHB Inactive HBsAg Carrier HBeAg– CHB (Precore Mutant) HBsAg++++ HBeAg++–– Anti-HBe––++ ALTNormal   HBV DNA (copies/mL) > 10 5 < 10 3 > 10 4 HistologyNormal/MildActiveNormalActive Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. 2001;120:1828-1853. clinicaloptions.com/hep

35. Annual Risk of HBV Progression HBeAg+ chronic hepatitis B HBeAg-Neg chronic hepatitis B Cirrhosis Decompensation HCC 5.0% 1.0%-2.0% 3.0%2.0% All HBsAg + individuals 0.4%  Factors linked with progression – Duration of “active”disease – Heavy alcohol use – Immune suppression (HIV) Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. clinicaloptions.com/hep

36. HBV DNA Level and Risk of HCC HBV DNA (copies/ml) Cumulative incidence of HCC <3001.30 300-99991.37 10,000-99,9993.57 100,000-999,99912.17 >1 million14.89 Chen C-J. JAMA 2006; 295:67-73.

37. HBV Treatment Guidelines HBeAg HBV DNA (IU/ml)* ALTManagement + < 20,000Normal # Follow, no treatment + ≥ 20,000Normal Consider biopsy; treat if diseased + ≥ 20,000ElevatedTreat – < 2,000Normal Follow, no treatment – ≥ 2,000Normal Consider biopsy; treat if diseased – ≥ 2,000ElevatedTreat *1 IU = 5.6 copies; # Normal ALT for men = 30 U/ml and for women = 19 U/ml Keeffe EB, et al. Clin Gastroenterol Hepatol.2006.

38. HBV/HIV Patient 41 yo gay white man with C3 HIV, hep B, cirrhosis eAg+, baseline HBV DNA 10 million copies/ml, ALTs in 40-50’s HIV well-controlled, CD4 787, HIV <30, on NVP, ddI, Kaletra (highly ARV experienced) Started on LAM 100 mg/d 9/05 Seen by me 6/06: VL 5.5 million, ALT 49 Any mistakes in treatment? What medication should we use next?

39. Goals of Therapy in Patients With Chronic HBV Infection Eradication of infection –HBsAg seroconversion –Undetectable HBV DNA Prevent complications of liver disease –Histologic progression to cirrhosis –Decompensated liver disease –Liver cancer clinicaloptions.com/hep

40. Therapeutic Endpoints HBeAg-positive patients (wild type) –HBeAg seroconversion is KEY –Sustained suppression of HBV DNA to low or undetectable levels –ALT normalization –Reduced necroinflammation on biopsy HBeAg-negative patients (precore and core promoter mutants) –HBeAg seroconversion not an endpoint –Sustained suppression of HBV DNA to low or undetectable levels –ALT normalization –Reduced necroinflammation on biopsy clinicaloptions.com/hep

41. Approved anti-HBV drugs and those in development DrugClassPhaseAnti-HIVActive against YMDD Interferon-  Immune modulator ApprovedYes Peg-IFN-  ImmuneApprovedYes LamivudineNucleosideApprovedYesNo AdefovirNucleotideApprovedWeakNo EntecavirNucleosideApprovedYes TenofovirNucleotideIYes FTCNucleosideIYesNo TelbivudineNucleosideIIINo ClevudineNucleosideIIINoYes DAPDNucleosideIIYes Nunez M, et al. Lancet Infect Dis 2005.

42. Responses to anti-HBV agents in HIV/HBV coinfected patients IFNLAMADVETVFTCTDF # pts87230355133200 HBV DNA ↓ 26%2.7 log4.7-6 log3.6 log-4.4 log E sero- Convert 9%11%7%--4% ALT normalize 12-20%30-50%35-66%49%-- Histology improve --33-50%--- Benhamou Y. J Hepatol 2006.

43. HBV Treatment Algorithm in HIV/HBV Coinfected Patients HBVsAg-positive ALT HBVeAg HBV DNA >10 4 Biopsy Normal Elevated Negative Positive No Yes Normal Hepatitis Rx Nunez M. Lancet Infect Dis 2005

44. Lamivudine (3TC, Epivir) Nucleoside analog Different dose for HBV (100 mg) monotherapy, use 300 mg for HIV+ and never alone Well-tolerated and cheap eAg conversion rate b/t 21-28% High rates of resistance! –47% develop YMDD mutation at 2 yrs, 90% at 4 yrs

45. Adefovir (Hepsera) Nucleotide analog At 10 mg/d dose, no HIV activity Effective for LAM resistant HBV, no cross- resistance Side effects: renal toxicity, Fanconi’s Syndrome

46. Tenofovir (Viread) Nucleotide analog not approved for HBV Perhaps more potent than Adefovir –48 wk mean decline in HBV DNA (log10) 4.4 vs 3.2 63% had HBV suppression by wk 48, 15% had anti-HBe seroconversion Rare cases of ADV resistance but TDF sensitivity Schildgen O. 2006 N Engl J Med 354:1807-12 Peters M. CROI 2005; Abstract 124.

47. Entecavir (Baraclude) Nucleoside analog No HIV activity Good for LAM failures –84% of patients had 2 log decline or <400 copies/ml after 24 wks Cross-resistance can occur w/ LAM Start w/ higher dose (1.0 mg/d) Entecavir in HIV/HBV patients

48. Peg-interferon (Pegasys) Long acting form of IFN, once weekly Pros: defined duration (48 wks), low resistance Cons: Many side effects, expensive, not for decompensated cirrhosis No data in HIV+, probably lower response than in HIV- In HIV-, PEG better than LAM –27% seroconversion, 4.5 log HBV DNA reduction, 3% sAg loss

49. Treatment Options for HIV/HBV Coinfected Patients Only HBV therapy indicated HBeAg-positivePegylated IFN Entecavir Adefovir HBeAg-negativeEntecavir Adefovir HIV and HBV therapy indicated HAART including TDF +/- LAM or FTC HAART + (ADV or ETV) Only HIV therapyAt least one HBV active drug to avoid flares Nunez. Lancet Infect Dis 2005.

50. Back to the patient 41 yo gay white man with C3 HIV, hep B, cirrhosis eAg+, baseline HBV DNA 10 million copies/ml, ALTs in 40-50’s HIV well-controlled, CD4 787, HIV <30, on NVP, ddI, Kaletra (highly ARV experienced) Started on LAM 100 mg/d 9/05 Seen by me 6/06: VL 5.5 million, ALT 49 Any mistakes in treatment? What medication should we use next?

51. Web Resources www.aasld.org www.hivandhepatitis.org www.hepwebstudy.org www.cdc.gov/ncidod/disea ses/hepatitis/c/index. www.idsociety.org

52. Good Reviews Sulkowski MS. Treatment algorithm for the management of hepatitis C in HIV-coinfected person. 2006. J Hepatol 44:S49-55 Nunez M, Soriano V. Management of patients coinfected with hepatitis B virus and HIV. 2005. Lancet Infect Dis 5:374-82 Tien P, Wright T. Management and treatment of hepatitis C virus infection in HIV-infected Adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office. 2005. Am J Gastro 100: 2338-54. Benhamou Y. Treatment algorithm for chronic hepatitis B in HIV-infected patients. 2006. J Hepatol 44:S90-94.

53. Thanks!