"Treatment of Viral Hepatitis - PowerPoint"
Treatment of Viral Hepatitis Paul Y Kwo, MD Associate Professor of Medicine Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine Human Hepatitis Viruses Human Hepatitis Viruses Virus Genome Genome Envelope Family / genus size (kb) HAV RNA 7.5 - Picornaviridae positive sense, hepatovirus single stranded, linear HBV DNA 3.2 + Hepadnaviridae partially double stranded, circular HCV RNA 9.6 + Flaviviridae positive sense, hepacivirus single stranded, linear HDV RNA 1.7 + Unclassified positive sense, (viroid), delta virus single stranded, linear HEV RNA 7.5 - Unclassified, positive sense, single togavirus and stranded, linear alpha virus-like Hepatitis B Virus Nucleic Acid: 3.2 kb DNA Classification: Hepadnaviridae Multiple serotypes and genotypes 42 nm A-H Enveloped 22 nm In vitro model: primary hepatocyte culture and HBsAg transfection of cloned HBV DNA 42 nm HBcAg In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte HBsAg and other tissues, human and HBV DNA other primates 22 nm Prevalence of HBsAg Carrier State >8% 2-8% <2% WHO Hepatitis B by Year, United States, 1966 - 2000 HBsAg 14 screening of pregnant Infant Immunization Cases per 100,000 Population Vaccine recommended 12 licensed women recommended 10 OSHA Rule enacted Adolescent 8 Immunization 6 recommended 4 Decline among Decline among injecting 2 MSM & HCWs drug users 0 1967 1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 2000 Source: NNDSS Year HBV: How Do People Get Infected? Hepatitis B is transmitted by contact with blood or body fluids of an infected person The main ways of getting infected with HBV are: Perinatal (from mother to baby at birth) Child-to-child transmission Unsafe injections and transfusions Sexual contact HBV is 50 to 100 times more infectious than HIV Household contact is a documented risk factor From http://www.who.int/vaccines/en/hepatitisb.shtml. Accessed 09/20/06. American Journal of Epidemiology Vol. 132, No. 2: 220-232. HBV: How Do People Get Infected? Asian Americans Non-Asian Americans Mother to baby at time of birth Adult sexual activity (~54% of cases) (most cases) Within household (virus can survive for at IV drug use (~20% of cases) least 7 days outside body) Reuse of nonsterilized needles and syringes in poor healthcare facilities Traditional medicine (acupuncture, coining, cupping) From http://liver.stanford.edu/Edu/Edu_stat.php. Accessed 09/10/06. Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W et al, eds. Epidemiology & Prevention of Vaccine-Preventable Diseases. 8th ed, Washington DC: Public Health Foundation; 2005:191-212. HBV - Epidemiology Risk of Chronic Infection 100 80 60 % Risk 40 20 0 Neonates Infants Children Adults Age at Infection Hepatitis B Virus Infection, United States New infections /year 1985-90 438,000 1999 125,000 Deaths from acute liver failure 1999 300 Persons ever infected (1990) 4.9% Persons with chronic infection 1.25 million HBV-related chronic liver disease 4% - 14% Deaths from chronic disease/year ~ 5,000 Life-time risk of death due to HCC or cirrhosis ~30% HBV - Natural History Cumulative Probability of Developing HCC in Patients with HBsAg + Compensated Cirrhosis 20 15 % 25 0 0 1 2 3 4 5 6 7 8 9 10 Year Fattovich, et al., Hepatology 1995; 21:77 HBV - Diagnosis Serological Markers Clinical Significance HBsAg Acute/Chronic infection Anti-HBc IgM Acute infection HBeAg High infectivity Anti-HBe Low infectivity Anti-HBs Immunity Anti-HBc IgG and HBsAg Chronic infection Anti-HBc IgG and anti-HBs Resolved infection Hepatitis B Virus Wild Type and Mutants Wild type Usual HBeAg (+) hepatitis Precore mutation (27% U.S. patients) Abolishes HBeAg production Core promoter mutation (44% U.S. patients) Down-regulates HBeAg production Treatment-induced mutations Lamivudine: M204V/I +/- L180M and others (YMDD) Adefovir: N236T and A181V/T Entecavir: I169, T184, S202 and M250 (only with treatment of patients with lamivudine mutations) HBV Genotypes HBV classified into 8 genotypes (A-H) A: North America, Western Europe and Africa B and C: Asia D: Southern Europe, Africa and India E: West Africa F: Central and South America and Alaska G: United States, France and Germany H: Central America B associated with less active disease, slower progression, and lower incidence of HCC than C A and B respond better to IFN than C and D Genotype does not predict on-treatment response to oral agents Natural Course of Chronic HBV Infection HBeAg Anti-HBe HBV DNA ALT Immune Immune Inactive Reactivation Tolerance Clearance Carrier HBV DNA During Different Stages of CHB MAJOR RESULTS MAJOR RESULTS HBeAg(+) patients HBeAg(+) patients with sustained HBeAg loss: (a) spontaneous, and (b) IFN-related Log10 HBV DNA (copies/mL) Log10 HBV DNA (copies/mL) 11 11 10 10 9 9 8 8 7 7 6 6 5 5 4 4 3 3 2 2 1 1 0 0 (a) (b) (a) (b) (a) (b) 1st 2nd 3rd Sample 1st 2nd 3rd Sample Chu CJ, et al. Hepatology 2002;36:1408-1415 REVEAL: Baseline HBV DNA and Liver Disease Progression Prospective, multicenter, observational cohort study 1991-1992: 7 Taiwanese townships Individuals aged 30-65 years eligible (N = 89,293) HCC-free individuals enrolled (n = 23,820) Excluded if cirrhotic within 6 months Cirrhosis Analysis HCC Analysis (n = 3774) (n = 3653) 2004: 42,115 PYs follow-up 2004: 41,779 PYs follow-up 395 cirrhotic patients (10.5%) 164 HCC patients (4.5%) Chen CJ, et al. JAMA 2006;295:65-73. Iloeje UH, et al. Gastroenterology 2006;130:678-686. REVEAL Study: HBV DNA Levels and Long- Term Outcomes Viral Load at Baseline < 300 (Undetectable) 10,000-99,999 1 Million 300-9,999 100,000-999,999 Cumulative incidence of HCC Multivariate-adjusted (%) (n = 3653) relative risk of cirrhosis (n = 3482) 20 12 10.6 9.7 10 14.89% 15 12.17% 8 10 6 4 3.6 5 3.57% 2.0 2 1.30% 1.37% 1.0 0 0 Chen CJ, et al. JAMA. 2006;295:65-73. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. HBV Indications for HBV vaccination HBIG and HB vaccine to infants of HBsAg+ mothers Routine vaccination of infants and adolescents Catch-up vaccination of children Vaccination of adults at risk of infection Surrogate Clinical Markers for Hepatitis B Outcomes Liver histology Improves Serum HBV DNA declines Prevention of Death, Cirrhosis, and HCC Seroconversion (loss of HBeAg, ALT normalization production of anti-HBe) Cirrhosis Reversal Following Lamivudine Rx in HBV Courtesy of Ian Wanless, MD. HBV Treatments 2007 Interferon or 4 oral agents Interferon Lamivudine Adefovir Pegylated IFN Telbivudine Entecavir Pros Finite duration of Oral Oral therapy Negligible side Effective against Durable response effects lamivudine-resistant post treatment mutants Resistant mutants Resistant mutants not not reported reported at 1 year Cons Injection Long / indefinite Long / indefinite duration of duration of therapy Frequent side therapy effects Long-term renal Resistant mutants toxicity unknown Higher with lamivudine/telbivudine Treatment Recommendations for HBeAg(+) Patients ALT HBV DNA Recommendations No treatment, monitor1,2,3 ≤2 × ULN + Grey zone: ALT 1–2 x ULN or intermittently elevated; liver biopsy → moderate/severe inflammation or advanced fibrosis → treatment1 >2 × ULN + Observe × 3–6 months; treat if no spontaneous HBeAg seroconversion1,2,3 Immediate treatment if bilirubin increases3 or decompensation1,3 HBV DNA: + defined as >100,000 copies/mL Guidelines: 1AASLD; 2EASL; 3APASL Baseline ALT and Response to Treatment of HBeAg(+) Patients 50 % HBeAg Seroconversion 40 Placebo LAM 30 IFN LAM + IFN 20 10 0 1-2 x ULN 2-5 x ULN > 5 x ULN Baseline ALT Perrillo RP, et al. Hepatology 2002;36:186-194. Treatment Recommendations for HBeAg(-) Patients ALT HBV DNA Recommendations ≤2 × ULN <100,000 copies/ml No treatment, monitor1,2,3 Grey zone: ALT 1–2 X ULN; HBV DNA 10,000 – 100,000 copies/mL Liver biopsy → moderate/severe inflammation or advanced fibrosis → treatment1 >2 × ULN >100,000 copies/ml Treatment1,2,3 HBV DNA: < or >100,000 copies/mL Guidelines: 1AASLD; 2EASL; 3APASL Treatment Algorithm Patients with Compensated Disease HBeAg Positive HBV DNA HBV DNA <20,000 IU/mL ≥20,000 IU/mL ALT Normal ALT Elevated • No treatment • Monitor ALT every 3-12 • Treat months (immune • Adefovir, entecavir, • Monitor every 6–12 months tolerant) peginterferon, and • Consider biopsy, if age possibly telbivudine are >35–40, and treat if first-line options significant disease Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Treatment Algorithm Patients with Compensated Disease HBeAg Negative HBV DNA HBV DNA <2,000 IU/mL ≥2,000 IU/mL ALT Normal ALT Elevated • No treatment • Monitor ALT and HBV • Treat DNA, or • Adefovir, entecavir, • Monitor every 6–12 months • Consider biopsy, since peginterferon, and ALT often fluctuates, possibly telbivudine are and treat if significant first-line options disease • Long-term treatment required (oral agents) Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Treatment Algorithm Patients with Compensated Cirrhosis HBV DNA HBV DNA HBV DNA <2,000 IU/mL (PCR) ≥2,000 IU/mL • Treat with adefovir or entecavir • May be a role for combination therapy • Significant clinical consequences associated with lamivudine resistance in this population • May choose to treat or observe • If treat: adefovir or entecavir, or combination Rx • May be a role for combination therapy Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Management of Antiviral Resistance HBV Prevention • Avoid unnecessary treatment • Initiate treatment with potent antiviral that has low rate of drug resistance or with combination therapy • Switch to alternative therapy in patients with primary non- response Monitoring • Test for serum HBV DNA (PCR assay) every 3-6 months during treatment • Check for medication compliance in patients with virologic breakthrough • Confirm antiviral resistance with genotype testing Antiviral HBV Drug Resistance Potential Treatment Resistant Drug Rescue Therapy Continue lamivudine and add adefovir or tenofovir* Lamivudine-R Switch to emtricitabine/tenofovir* Continue adefovir and add lamivudine or telbivudine Adefovir-R Switch to or add entecavir (if no prior LAM-R) Switch to emtricitabine/tenofovir* Switch to or add adefovir or tenofovir* Entecavir-R Switch to emtricitabine/tenofovir* Continue telbivudine and add adefovir or tenofovir* Telbivudine-R Switch to emtricitabine/tenofovir* *Not approved by FDA. Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962, and Lok ASF, McMahon BJ. Hepatology. 2007;45:507-539. Bottom Line: When to Start Therapy: 1) Elevated HBV DNA Level 2) ALT Level above ULN The Threshold and Guidelines for treating HBV are falling and dynamic Hepatitis C: A Global Health Problem 170-200 Million Carriers Worldwide Far East Asia Western Eastern 60 M Europe Europe US 10 M 5M 3-4 M South East Asia 30-35 M Americas Africa 12-15 M 30-40 M Australia 0.2 M World Health Organization, 1999. Hepatitis C Virus Infection in the US New infections (cases)/year 1985–1989 242,000 2003 30,000 Deaths from acute liver failure Rare Persons ever infected (1.8%) 3.9 million (3.1–4.8)* Persons with chronic infection 2.7 million (2.4–3.0)* HCV-related chronic liver disease 40%–60% Deaths from chronic disease/year 10,000 *95% Confidence Interval Prevalence of HCV Antibody NHANES III 90s 00s 2,000,000 Prevalence 1,500,000 1,000,000 500,000 0 6-11 12-19 20-29 30-39 40-49 50-59 60-69 70-79 80+ Age distribution Adapted from Alter MJ, et al.,. N Engl J Med. 1999;341:556–562. Risk Factors for Acute Hepatitis C United States, 1991-1995 Injection Drug Use 43.0% Other High Risk* 30.0% *Other High Risk Unknown 1.0% Household 3.0% 16% drug related •11% previous drug use Occupational 4.0% not within last 6 months • 5% intranasal cocaine use Transfusion** 4.0% 4% history of STDs **None in 1995 1% prison Sexual (Multiple Partners) 15.0% 9% lower socio-economic status (fewer years of education) Alter MJ. Presented at the NIH Consensus Development Conference, March 24, 1997. HCV Infection Testing Algorithm for Diagnosis of Asymptomatic Persons EIA for Anti-HCV Negative STOP (non-reactive) Positive (repeat reactive) OR Negative RIBA for Anti-HCV RT-PCR for HCV RNA Negative Indeterminate Positive Positive Additional Laboratory Medical STOP Evaluation (e.g. PCR, ALT) Evaluation Negative PCR, Positive PCR, Normal ALT Abnormal ALT Adapted from Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset. Accessed 01/18/03. MMWR 1998;47 (No. RR 19) HCV Genotypes and Subtypes Developed countries 2 Americas + Western Europe South Africa 5 1 Middle East North Africa 4 IVDU Asia 3 Simmonds P, Journal of Hepatology, 1999 6 Chronic HCV Infection HCV RNA 1000 + + + + + + + + + + + + + 800 ALT (U/L) Anti-HCV 600 Chronic 400 Symptoms Hepatitis C 200 0 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Weeks Months Time After Exposure Hoofnagle JH. Hepatology.1997;26:15S-20S. Hepatitis C: Spectrum of Disease Acute HCV Infection 85% 15% Chronic HCV Infection Recovery Severe Moderate Mild Cirrhosis Chronic Hepatitis HCC End-Stage Liver Disease Hoofnagle JH. Hepatology. 1997;26:15S-20S. HCV-related fibrosis, cirrhosis and hepatocellular cancer Why Do We Treat Chronic HCV? 1000 HCC 800 4+ ALT 3+ 2+ ALT (U/L) 1+ 600 Fibrosis Cirrhosis Anti-HCV 400 HCV RNA 200 0 0 0.5 1 2 5 10 15 20 25 30 35 40 45 50 Years After Exposure Hoofnagle JH. Hepatology 2002;36:S21-S29. Who Should Be Treated for Hepatitis C? • Those with detectable HCV RNA, liver biopsy with fibrosis and/or inflammatory changes • Patients with cirrhosis without decompensation • Acute hepatitis C • People with significant extra-hepatic manifestations of hepatitis C • A normal ALT may mean less severe disease, but treatment should be individualized, especially with improved cure rates HCV Therapy: Definitions Rapid Virologic response : Undetectable HCV RNA at week 4 of therapy: These individuals may require shorter treatment duration Early virologic response (EVR): 2 log (99%) reduction in HCV RNA level during therapy, usually at week 12 Accurately predicts non-response to therapy, need to use same assay Sustained virologic response (SVR): Undetectable HCV RNA by PCR testing 24 weeks after stopping therapy The best definition of cure at this time Non-response: Failure to clear HCV RNA during therapy, can be determined during weeks 12-24 Use of Viral Kinetics to Define On-treatment Predictors of Response HCV RNA 4 12 24 Weeks Earlier viral clearnace predicts greater liklihood of sustained response (cure) Peginterferon alfa-2b/Ribavirin Virologic Response 100 IFN/RBV PEG IFN 0.5 + RBV 1000-1200 80 PEG IFN 1.5 + RBV 800 80 82 79 SVR (%) 60 54* 47* 47 40 42† 33† 34 20 0 All Genotype 1 Genotype 2/3 *P = .01; †P = .02 Manns MP, et al. Lancet. 2001. 358:958 % of patients with undetectable HCV-RNA SVR in US Genotype 1 Patients (ITT) 80 60 40 41 38 40 20 0 PEG α-2b 1.5 + R, PEG α-2b 1.0 + R, PEG α-2a 180 + R, N=1019 N=1016 N=1035 PEG-IFN -2b 1.5/RBV vs PEG-IFN -2a 180/RBV, p-value 0.57 PEG-IFN -2b 1.5/RBV vs PEG-IFN -2b 1.0/RBV, p-value 0.20 86 2008: “Tailored” Treatment for Genotype I • A 24 week dosage regimen with Peg-IFN/RBV appropriate for genotype 1 CHC patients with a rapid viral response (RVR) • A 72 week dosage regimen with Peg-IFN/RBV is appropriate for “slow responders” • Higher doses of RBV may be appropriate for certain genotype 1 patients • Ribavirin dose will be most important till introduction of new molecules for HCV Should First Viral HCV-RNA Assessment be Done at Week 4? • Goal with week 12 assessment: Identify non- responders early during therapy to determine if therapy should be discontinued – Avoids additional morbidity in those who will not respond – Reduces cost • In 2008, – Can we make a determination at 4 weeks as to who is likely to respond? – Can we identify those genotype 1 patients who might respond with only 24 weeks of therapy? Shorter Treatment Duration for HCV-1 and Rapid Virologic Response (RVR) PEG-IFN 180 g/wk plus RBV 1,000-1,200 mg/day 366 treatment naïve HCV-1 and HCV-4 pts received standard PEG + RBV 79 (22%) W4 HCV RNA – patients received a total of 24 wks of therapy 100% 92% 92% 80% 74% 73% 67% 24 wks may suffice 60% for HCV-1 with LVL and early fibrosis if RVR 40% 20% 0% ITT LVL HVL F0-2 F3-4 Ferenci et al. Hepatology 2005;42(suppl 1):218A. High Dose Ribavirin for HCV Is there a role in non-responders? Genotype 1 naïve patients 48 weeks of treatment 3 arms : Standard PEG IFN alpha 2 b with RBV 800-1400; RBV 800-1400, EPO; RBV1000-1600, EPO 70 60 * 50 PEG RBV 800- 40 1400 PEG RBV 800- 30 1400 EPO 20 PEG RBV 1000- 1600 EPO 10 0 EVR EOT SVR Shiffman ML, Price A, Hubbard S, et al. Treatment of chronic hepatitis C virus (HCV) genotype 1 with peginterferon alfa-2b (PEGIFN), high weight based dose ribavirin (RVN) and epoetin alfa (EPO) enhances sustained virologic response (SVR). Program and abstracts of the 56th Annual Meeting of the American Association for the Study of Liver Diseases; November 11-15, 2005; San Francisco, California. Abstract 55 What patients benefit from a longer duration of treatment? Non-response to treatment (NR) HCV RNA Level Partial Response to treatment (NR) Slow response to treatment (SVR, NR or relapse) RVR EVR (SVR or relapse) 4 12 24 Treatment Week: PEG IFN Ribavirin •Those with slow response, early virologic response may benefit from treatment duration beyond 48 weeks (decreasing relapse) •? partial responders TeraViC-4 Study: Prolonged therapy reduces relapse in those without RVR 510 patients, 78% genotype 1,4 PEG IFN alfa 2a 180 mcg, RBV 800 mg Those without RVR at week 4 randomized (326) to 48 vs 72 weeks 70 HCV RNA undetected % 61 61 60 p=.01 p=.003 48 weeks 50 45 44 40 72 weeks 32 30 28 48 weeks 20 genotype 1 10 72 weeks genotype 1 0 EOT SVR SVR Genotype 1 Sanchez-Tapia SJM. Hepatology 2004;40:218A. Abstract No. 126. New Strategic Approaches • Improved pharmacokinetics – eg, PEG-IFN • Improved routes of administration – albumin-interferon alpha (fusion protein of IFN and albumin) • Reduced toxicity of RBV – eg, viramidine, VX 497 • New molecular targets – protease inhibitors, helicase, polymerase inhibitors • VX-950, SCH 503034 , MK-7009 (all undergoing clinical trials here at IU) • Antifibrotics/immune modulators/apoptosis inhibitors – eg, IFN-, low-dose IFN, thymosin, IDN-6556 (caspase inhibitor) • Supportive agents – eg, epoetin, G-CSF, antidepressants Have a referral for study or non-study patient to be seen? firstname.lastname@example.org or call 317-278-1187 Maintenance Therapy Indications Goals Nonresponse Delay progression to best available Prevent therapy cirrhosis, Advanced decompensation, HCC fibrosis or Avoid liver transplantation cirrhosis Improve survival CO-PILOT: 0.5 mcg/kg PEG Interferon alfa-2b EPIC: 0.5 mcg/kg PEG Interferon alfa-2b HALT-C: 90 mcg Peg Interferon alfa-2a HALT C results 34.1% of patients in the pegylated interferon maintenance arm and 33.8% of the control group had reached one of the study endpoints (hazard ratio 1.01; P = 0.91; not a significant difference). Although mean serum ALT and HCV RNA levels decreased significantly with treatment (both P < 0.0001), as did necroinflammatory changes on liver biopsy (P < 0.0001), there was no significant difference observed in rates of any of the primary outcomes: Death: 6.6% in the treatment group vs 4.6% in the control group; Hepatic decompensation: 14.3% vs 13.2%, respectively; HCC: 2.8% vs 3.2%; Increased fibrosis: 28.2% vs 31.9%. HCV-Related Liver Transplantation in 2008 HCV is leading indication for liver transplantation 500,000 with HCV related cirrhosis in US Recurrence is universal; progressive liver injury occurs Posttransplantation natural history is variable – Short-term survival is good – Long-term natural history is not as good Management of immunosuppression is controversial IFN or RBV monotherapy has limited efficacy Combinations of RBV + IFNs or PEG IFN lead to sustained response rates that are lower than in non-transplant patients Selected Herbs Milk Thistle Silymarin (Silybum marianum) Used for almost 2000 years Reemergence for the therapy of liver disease Virtually every patient asks about it Selected Herbs Milk Thistle (cont’d) Antioxidant/anti-inflammatory effects Inhibits lipid peroxidation Decreases the activity of tumor promoters Chelates iron Most of the existing clinical trials in chronic liver disease have flaws Lack of clinical studies in patients with HCV infection Bhatia N, et al. Cancer Lett. 1999;147:77. Flora K, et al. Am J Gastroenterol. 1998;93:139. Patrick L. Alternative Med Review. 1999;4:220. What I Tell Patients Who Are Diagnosed with Hepatitis C • Hepatitis C is the major cause of chronic hepatitis in the United States • Hepatitis C is transmitted primarily by contact with infected blood or blood products administered through the blood stream • Sexual transmission and mother-to-fetus transmission are rare (Centers for Disease Control does not consider HCV to be a sexually transmitted disease) • This disease is difficult to transmit to family members • Alcohol consumption should be minimized, abstinence is recommended •Insulin resistance reduces efficacy of interferon based therapy •Acute hepatitis C is curable almost 100% of the time What I Tell Patients Regarding Transmission of Hepatitis C • You should refrain from donating blood, organs, tissues or semen • With multiple sexual partners, the use of latex condom should be encouraged • Sexual partners of infected patients should be tested for HCV • Do not share razors and toothbrushes, but it is not necessary to avoid sharing meals or utensils • HCV patients can participate in any social, education or employment activities •Pegylated Interferon and ribavirin remains the standard, and likely will not be replaced for 5 years What I Tell Patients Regarding Treatment of Hepatitis C HCV can be cured in over half of all cases Therapy is evolving: week 4 PCR clearance suggests shorter duration of treatment may be sufficient with no sacrifice in SVR for all genotypes 24 weeks for genotype 1 low viral load 12 weeks for genotypes 2 and 3 Extending therapy beyond 48 weeks in those with who are slow responders may reduce relapse Future therapies appear promising though interferon will remain the backbone of therapy