Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Human cytomegalovirus wikipedia , lookup
Herpes simplex virus wikipedia , lookup
Sexually transmitted infection wikipedia , lookup
Epidemiology of HIV/AIDS wikipedia , lookup
Diagnosis of HIV/AIDS wikipedia , lookup
Antiviral drug wikipedia , lookup
Microbicides for sexually transmitted diseases wikipedia , lookup
What About Alcohol? Chance Of Getting Cirrhosis Non-Drinker Hepatitis C Non-Drinker Drinker Without Hepatitis C Drinker With Hepatitis C Coinfection peg-IFN/RBV Treatment Studies: Summary Study ACTG A5071 APRICOT RIBAVIC SVR % for 27% GT 1 40% 27% D/C Rate 12% due to AEs 15% 31% Low and High HCV RNA: APRICOT %SVR Low HCV RNA High HCV RNA (< 800,000) (>800,000) Gentoype 1 62% 18% Genotype 2,3 62% 65% Transmissibility through contaminated injections • HBV 30% • HCV 3% • HIV 0.3% Hepatitis B Virus • Member of Hepadnaviridae that primarily infects liver cells • Known carcinogen • 100 times more infectious than HIV • 10 times more infectious than HCV Geographic Distribution of Chronic HBV Infection HBV Genotypes F D A D A,B,C,D C C D D E D Bj Ba F F A A,B,C,D This is an oversimplification as populations are not static… Chronic HBV: Clinical Features • Symptoms – General: fatigue, anorexia, arthralgia, nausea – Advanced: ascites, edema, bleeding GE varices, bruising, enlarged spleen, jaundice, spider nevi, muscle wasting • Symptoms may not correlate with liver biopsy findings HBV DNA HBsAg HBeAg ALT (U/L) + + +/– Normal to Anti-HBc (IgM) and Anti-HBs will also be negative for patients with chronic hepatitis B. Dienstag, et al. In: Harrison’s Principles of Internal Medicine, 15th ed. Chap 297. Mahoney. Clin Microbiol Rev. 1999;12:351-366. McMahon. Semin Liver Dis. 2004;24:17-21. CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 9th ed. 2006. Natural Progression of CHB 15%–40% of CHB patients may experience disease progression Liver Cancer (HCC) 5%–10% 10%–15% in 5 yr Chronic Infection 30% Cirrhosis Liver Transplantation Death 23% in 5 yr Acute flare Liver Failure Adapted from: Fattovich, et al. Gastroenterology. 2004;127:S35-S50. Torresi, et al. Gastroenterology. 2000;118:S83S103. Fattovich, et al. Hepatology. 1995;21:77-82. Perrillo, et al. Hepatology. 2001;33:424-432. Influence of HBV on HIV CONFLICTING DATA • Increased rate of HIV progression to AIDS? 1 • No change in progression? 2 • Cohort studies suggest that HBV does not appear to influence the progression of HIV. Ref : 1.Eskild A, Magnus P, et al. Hepatitis B antibodies in HIV-infected homosexual men are associated with more rapid progression to AIDS. Aids 1992:6:571-4 2. Diamondsstone LS, Blakly SA, et al. Prognostic factors for all-cause mortality among hemophiliacs infected with human immunodeficiency virus. Am J Epidemiol 1995:142:304-13 Influence of HIV on HBV • Lower rates of clearance of HBeAg • Increased serum HBV DNA viral load 1 • Reactivation of hepatitis in asymptomatic carriers • Increased liver injury • Faster fibrosis cirrhosis and HCC • Higher mortality and morbidity Ref: 1. Perillo RP, Regenstein FG, et al. Chronic hepatitis B in asymptomatic homosexual men with antibody to the human immunodeficiency virus. Ann Intern Med 1986:105:382-3 HIV Co-infection Increases the Risk of End-Stage-Liver-Disease (ESLD) due to HBV • MACS, 4,967 men – HIV, 47% – HBV, 6% (n=326) – HIV/HBV, 4.3% (n=213) • HIV/HBV: 17-fold higher risk of liver death compared to HBV alone Liver Mortaility by HIV and HBV Status 14.1 15 10 5 0 0.8 1.7 No HIV or HBV HBV only HIV only 0 • Alcohol and low CD4 even increase the risk Thio C et al. Lancet 2002;360:9349. HIV and HBV When to Treat • HBeAg + • HBeAg – HBV DNA (IU/mL) 20,000 2,000 1 IU/mL = 5 to 6 copies/mL Treatment Options for CHB Interferon -alfa Immunomodulatory action Antigen presenting cell T helper cell B cell Cytotoxic T cell Antiviral action Natural killer cell Antiviral action Nucleoside/ nucleotide analogues Treatment Options AVAILABLE DRUGS • Nucleoside/ nucleotide analogues – LAM(3TC), ADV, ETV, FTC, TDF • Newer agents TELBUVIDINE (LdT),CLEVUDINE, PREDOFOVIR • Interferons - conventional -pegylated Aims of Therapy for HBeAg-positive CHB • Short-term measurable ‘surrogate’ markers of treatment efficacy – recommended endpoint: HBeAg seroconversion1 – other endpoints: HBV DNA suppression, ALT normalisation • Long-term goals – prevent/stop/reduce • liver necrosis • progression to cirrhosis, decompensated cirrhosis or HCC • Ultimate goal – HBsAg seroconversion – prolong ‘event-free’ survival 1. Lok, McMahon. Hepatology 2004 (AASLD Guidelines) Treatment of HBeAg-Negative Chronic Hepatitis B • With nucleotide/nucleoside analogs • With interferons (conventional/pegylated) Challenges Of Therapy • Rational drug use – Both require treatment – Treat HBV alone or treat HIV alone • Screening? • Liver biopsy? • Treatment complications and their management • Viral resistance Lamivudine (LAM,3TC) Monotherapy for HBV • Resistance rates (HBV) 1st year 15 – 32% 2nd year 38% 3rd year 56% 4th year 67% Emergence of mutants associated with phenotypic resistance, viral breakthrough, with frequent hepatic failure. Adefovir (ADV) Monotherapy for HBV • Resistance rates (HBV) • 70 HBeAg negative patients 5 years of therapy with ADV 1 year 0% 2 years 3% 3 years 11% 4 years 18% 5 years 29% Hadziyannis et al Hepatology 2005; 42:754 Entecavir versus Adefovir: Mean HBV DNA Through Week 24 12 Entecavir (n=33) Adefovir (n=32) Mean HBV DNA by PCR (log10 copies/mL) 10 8 6 * 4 2 log10(300) copies/mL 0 0 14 28 42 56 70 84 Days *P<0.0001, primary efficacy endpoint. Leung N, et al. 57th AASLD. Boston, 2006. Abstract 982. 91 98 112 126 140 154 168 Tenofovir vs Adefovir in HBeAg-Positive Patients: HBV DNA <400 Copies/mL 100 Tenofovir DF (n=176) Adefovir (n=90) 90 76% Patients (%) 80 70 60 P<0.001 50 40 30 13% 20 10 0 0 4 8 12 16 20 24 28 Weeks on Study ITT: missing=failure. Heathcote EJ, et al. 58th AASLD. Boston, 2007. Abstract LB6. 92 32 36 40 44 48 Tenofovir vs Adefovir in HBeAg-Negative Patients: HBV DNA <400 Copies/mL 93% 100 Tenofovir DF (n=250) Adefovir (n=125) 90 P<0.001 Patients (%) 80 70 60 63% 50 40 30 20 10 0 0 4 8 12 16 20 24 28 Weeks on Study ITT: missing=failure. Marcellin P, et al. 58th AASLD. Boston, 2007. Abstract LB2. 93 32 36 40 44 48