Nothing to disclose. Screening for and treatment of Hepa11s B and C 2/18/15

Transcription

1 Screening for and treatment of Hepa11s B and C Lisa Winston, MD University of California, San Francisco San Francisco General Hospital Nothing to disclose. 1

2 Hepa11s B Epidemiology Pathogenesis Lecture outline Screening Treatment Evalua1on for hepatocellular carcinoma (HCC) Preven1on Chronic Hepa11s B (HBV) what are the numbers? Common 1.25 million in U.S. and 350 million worldwide Mortality In men with perinatal infec1on, up to 40% risk of death from liver disease deaths/year in U.S. 600,000 deaths/year worldwide Weinbaum CM, et al. MMWR. 2008;57(RR-8); mmwr/preview/mmwrhtml/rr5708a1.htm 2

3 HBV Transmission Worldwide Perinatal transmission Infec1on during youth U.S. Injec1on drug use Sexual transmission Natural history of hepa11s B infec1on % Hepatic decompensation Acute hepatitis B infection Resolved hepatitis B HBsAg-/Anti-HBs+ Chronic active infection Often HBeAg+ Perinatal: 90% 1-5 yrs: 20-50% Adult: < 5% Chronic hepatitis B infection HBsAg+/ Anti-HBs- Inactive carrier state HBeAg- Anti-HBe+ Cirrhosis HCC 3

4 Typical course of perinatally acquired HBV infec1on HBV DNA AST/ALT IMMUNE TOLERANCE (10-30 years) IMMUNE CLEARANCE NON-REPLICATIVE PHASE (Inactive carrier state) Serological findings in acute HBV infec1on (adult) Estimated 30-50% of adults are symptomatic HBV DNA IgG anti-hbc IgM anti-hbc Eleva,on in AST/ALT HBsAg Anti-HBs Window period 4

5 Serological findings in chronic HBV infec1on HBV DNA IgG anti-hbc HBsAg HBeAg Eleva1on in AST/ALT IgM anti-hbc Chronic active infection anti-hbe Inactive carrier state Recommenda1ons for HBV screening High prevalence area High- risk behaviors/condi1ons Preven1on of transmission to others Immunosuppression Weinbaum CM, et al. MMWR. 2008;57(RR-8);

6 Recommenda1ons for HBV screening High prevalence area: Born in countries with 2% HBsAg prevalence U.S.- born, parents born in regions 8% HBsAg High- risk behaviors/condi1ons: IDU, MSM, hemodialysis Preven1on of transmission to others Donors of blood, plasma, organs, 1ssues, sperm; pregnant women Immunosuppression Including HIV and plan for immunosuppressive therapy Weinbaum CM, et al. MMWR. 2008;57(RR-8); rr5708a1.htm 6

7 Hepa11s B flares and immunosuppression Who? HBsAg+ HBsAg- / an1- HBc+ / HBsAby- (selec1ve) HBsAg- / an1- HBc+ / HBsAby+ (very selec1ve) Why? Increased viral replica1on during immunosuppression; flare occurs with immune recons1tu1on What segngs? HIV aher start of an1retrovirals Cancer chemotherapy, cor1costeroids Immune modulators rituximab, TNF inhibitors How to screen for asymptoma1c hepa11s B infec1on? HBsAg iden1fy risk for transmission, liver disease, flares An1- HBs iden1fy those who need vaccina1on An1- HBc iden1fy risk for reac1va1on in selected segngs 7

8 Interpreta1on of HBV serologies HBsAg An,- HBc, total An,- HBc, IgM An,- HBs Interpreta,on Never infected Chronic infec,on Acute infec,on* Resolved infec,on, immune Immunized Mul,ple possibili,es *Anti-HBc, IgM+ can be seen in flares during chronic HBV infection A 63 yo man with remote h/o IDU and current heavy alcohol use has labs sent because his AST and ALT are abnormal (AST = 101, ALT = 53). The results are HepBsAg neg, an1- HepBsAby neg, an1- HepBcIgM neg, an1- HepBc total (IgG) pos. What is the most likely explana1on? 1. Window period 2. Resolved infec1on 3. Chronic infec1on 4. False posi1ve an1- HepBc total 8

9 What to do with isolated an1- HBc? Resolved infec1on Remote: low (non- detectable) an1- HBs Acute: just conver1ng to an1- HBs (window) an1- HBc, IGM+ Chronic infec1on with nega1ve HBsAg False posi1ve an1- HBc How to sort this out when needed? Vaccinate Wait, repeat tes1ng Check HBV DNA Once chronic hepa11s B is diagnosed Characterize viral infec1on Disease ac1vity Stage of disease Comorbidi1es HBV DNA HBeAg/an1- HBe AST/ALT Liver func1on tes1ng HCC screening Hep A, C, (D), HIV, ETOH 9

10 Chronic infec1on characteriza1on and risks Chronic hepatitis B infection* HBV DNA (> 20K) Elevated ALT Biopsy inflammation 1-5%/yr Cirrhosis Chronic active state HBeAg+ 3%/yr 10-20%/yr * Must have HBsAg+ x 2, 6 months apart Inactive carrier state 2-5%/yr HBeAg- HBV DNA (< 2K) Normal ALT Biopsy no inflammation 0.4%/yr HCC Hepatic decompensation Goals of treatment Primary goal Suppression of HBV DNA replica1on à Stop immune- mediated hepa1c inflamma1on à Prevent cirrhosis, HCC, and hepa1c failure v Secondary endpoint Convert to inac1ve carrier state 10

11 Who to treat for HBV infec1on? 1. Ac1ve disease = HBV- mediated hepa11s ALT > 2X ULN +/- inflamma1on/fibrosis on biopsy plus Ongoing viral replica1on 2. Cirrhosis with viral replica1on 3. Acute HBV mediated hepa1c decompensa1on 4. Pa1ent undergoing immune suppression Why not treat everyone with chronic HBV infec1on? Many would not develop complica1ons Inac1ve carrier state Treatment not always effec1ve Ineffec1ve treatment can lead to resistance Treatment associated side effects Cost 11

12 2/18/15 How to treat hepa11s B? Boost the immune response Interferon alpha or pegylated interferon alpha 2a Benefit: fixed dura1on of treatment May be used for HBV- associated glomerulonephri1s and polyarteri1s nodosa Risk: side effects An1virals (inhibit DNA synthesis) Benefit: low toxicity Risk: possible life- long treatment, resistance Transplant NEJM 2008;359:

13 Recommended treatments for chronic HBV infec1on No cirrhosis Entecavir or tenofovir or PEG- IFN- α Cirrhosis Compensated: Entecavir or tenofovir Decompensated: Entecavir or tenofovir plus transplant evalua1on Lok and McMahon, AASLD Practice Guideline; Hepatology: 2009 March 6, 2012 Screening for hepatocellular carcinoma is controversial One randomized controlled trial in China (HBsAg+ subjects) showed benefit Used ultrasound and AFP Concerns that analysis method not valid Another study using AFP only no benefit Most people in U.S. for whom screening recommended have cirrhosis due to HCV or ETOH 13

14 Which pa1ents with chronic HBV (HBsAg+) should be screened for HCC? Asian men > 40 years, Asian women > 50 years Cirrhosis Family history of HCC Africans > 20 years Any person > 40 years with persistent or intermipent ALT eleva1on and/or HBV DNA > 2000 Lok and McMahon, AASLD Practice Guideline; Hepatology: 2009 How to screen for HCC and at what frequency? How to screen? Ultrasound Sensi1vity and specificity >> AFP How frequently to screen? Every 6 months Bruix and Sherman, AASLD Practice Guideline HCC; Hepatology: 2010 Lok and McMahon, AASLD Practice Guideline Hepatitis B; Hepatology:

15 Preven1on of Hepa11s B Immuniza1on Rou1ne childhood immuniza1on Healthcare workers, MSM, IDU, HIV infec1on, people receiving hemodialysis, many with diabetes, chronic liver disease HBIG Maternal transmission Post- exposure prophylaxis (blood, sex) Transplanta1on HBV take home points Test pa1ents at high- risk for infec1on and high- risk of complica1ons from infec1on Time of disease acquisi1on ohen dictates course Screen with HBsAg, an1- HBs, and an1- HBc prior to immunosuppression Many pa1ents with chronic hepa11s B appear to benefit from treatment HCC screening is controversial 15

16 Hepa11s C Epidemiology Clinical disease Lecture outline Screening Assessment disease stage Treatment Hepa11s C (HCV) significance Common 180 million infected worldwide 3.2 million in U.S. with chronic infec1on Morbidity #1 cause of chronic liver disease in U.S. #1 reason for liver transplant in U.S. Mortality 8,000-13,000 deaths/year in U.S. 16

17 Transmission of HCV Blood exposure Sexual exposure Ver1cal transmission No vaccine No post-exposure prophylaxis MMWR Morb Mortal Wkly Rep Jul 22;60(28): Incidence of HCV infec1on in the U.S. CDC. Surveillance for Acute Viral Hepatitis -- United States, MMWR.2006 CDC. Viral Hepatitis Statistics and Surveillance,

18 Natural history of HCV infec1on and liver disease progression Acute infection 15-45% Resolved 75-95% Stable Less than 1/3 symptomatic 55-85% Chronic infection 5% per year 5%-25% over 20 years Cirrhosis 3% per year Hepatic decompensation HCC Extra- hepa1c manifesta1ons HCV Essen1al mixed cryoglobulinemia Deposi1on of immune complexes small and medium vessels Palpable purpua, arthralgias, membranoprolifera1ve glomerulonephri1s, neurologic disease Autoimmune disorders Autoan1bodies (> 60%), thyroid disease, sialadeni1s Other cutaneous disease Porphyria cutanea tarda, lichen planus Lymphoma, diabetes mellitus 18

19 Recommenda1ons for HCV Screening Birth cohort screening: persons born % of U.S. popula1on Three fourths of HCV infec1ons and HCV mortality An1body prevalence 3.25% (overall prevalence ~ 1.5%) MMWR August 17, 2012 / 61(RR04);1-18 Recommenda1ons for HCV screening Recommended Not Recommended Current or past IDU Clogng factor concentrates before 1987 Current or past hemodialysis Persistently abnormal ALT Transfusion or organ transplant before 1992 Children born to HCV posi1ve women Recognized exposure, e.g. needles1ck HIV infected Healthcare workers Pregnant women Household contacts of HCV posi1ve persons General public Uncertain Other transplant recipients Non-IDU illicit drug use Tattoos or body piercings Multiple sex partners Long term sex partners of HCV+ 19

20 How to test for HCV infec1on? HCV IgG (EIA) - Pre- test probability for chronic HCV Cleared infec,on vs. (False posi,ve) Chronic HCV RNA HCV High (unexplained liver disease) Immunosuppressed Concern for acute HCV Low No HCV infec,on Repeat HCV RNA in 4-6 mo HCV RNA How to evaluate a pa1ent with chronic HCV infec1on? Genotype virus Evaluate for co- morbidi1es that Accelerate disease May influence treatment choice Assess for hepa1c fibrosis 20

21 HCV genotyping 6 genotypes have been iden1fied Genotype 1: most common in U.S. and Europe Determine type of treatment Predict likelihood of response to treatment Much less of an issue Catalysts of HCV disease progression Alcohol: < 140 g (~10 beers)/wk Abs1nence recommended Metabolic syndrome/hepa1c steatosis Aim for ideal BMI Daily marijuana use Abs1nence recommended HIV co- infec1on: CD4 count fibrosis Start ART Ostapowicz, Hepatology. 1998;27(6): Kallwitz, Clin Gastroenterol Hepatol. 2010;8(1):72-8. Hezode, Gastroenterology. 2008;134(2): Thein, AIDS. 2008;22(15): Screen and immunize -Hep A -Hep B 21

22 Why assess for hepa1c fibrosis? Best marker to predict progression to cirrhosis Helps guide urgency of treatment Liver biopsy was gold standard Non- invasive tes1ng is becoming more common Serum (mul1- lab panels) Radiographic - transient elastography to assess liver s1ffness FibroScan approved by FDA in 2013 Screening for HCC in those with HCV Only screen when cirrhosis present Controversial (perhaps even more than with HBV) Ultrasound every 6 months 22

23 HCV treatment Now, greatest barrier is cost New guidelines Website launched 1/29/14 Commiped to regular updates Updated January 9,

24 HCV Direct Ac1ng An1virals Many drugs in clinical trials! J Viral Hepat 2012;19: Direct Ac1ng An1viral Profile Resistance profile Pan- genotypic efficacy Efficacy Adverse Events Drug- drug interac1ons NS3 1 NS3 2 NS5A 1 NS5A 2 NS5B nucleoside NS5B Non- nuc Good profile Average profile Poor profile 1: 1 st generation 2: 2 nd generation Slide courtesy of Dr. Timothy Morgan 24

25 What percentage of pa1ents relapse aher sustained viral response (SVR) at 12 weeks? 1. 40% 2. 20% 3. 10% 4. < 10% 25

26 Goals of HCV therapy Sustained viral response (SVR) Absence of detectable HCV RNA at least 12 weeks aher the end of treatment Represents virologic cure Reduce mortality, end- stage liver disease, and hepatocellular carcinoma Priori1zed treatment Compensated cirrhosis Advanced fibrosis Liver transplant recipients Severe extrahepa1c manifesta1ons HCV 26

27 Drugs recommended in current guidelines PEG- IFN mostly in alterna1ve regimens Ribavirin Sofosbuvir NS5B polymerase inhibitor Simeprevir NS3/4A protease inhibitor Ledipasvir (with sofosbuvir Harvoni) NS5A phosphoprotein inhibitor Paritaprevir/ritonavir/ombitasvir + dasabuvir (Viekira Pak) NS3/4A protease inhibitor, pharmacologic booster peritaprevir, NS5A inhibitor + nonnucleoside NS5B polymerase inhibitor Expected outcome HCV treatment > 90% will have SVR- 12 (cure) 27

28 Genotypes 1a and 1b - ini1al Ledipasvir/sofosbuvir (Harvoni) 12 weeks Paritaprevir/ritonavir/ombitasvir + dasabuvir (Viekira Pak) 12 weeks 1a with cirrhosis: dura1on 24 weeks 1b with cirrhosis: dura1on 12 weeks + ribavirin Sofosbuvir + simeprevir 12 weeks 1a: +/- ribavirin 1a and 1b with cirrhosis: dura1on 24 weeks Genotype 2 - ini1al Sofosbuvir + ribavirin 12 weeks Extend to 16 weeks with cirrhosis 28

29 Genotype 3 - ini1al Sofosbuvir + ribavirin 24 weeks Genotype 4 - ini1al Ledipasvir/sofosbuvir (Harvoni) 12 weeks Paritaprevir/ritonavir/ombitasvir + ribavirin 12 weeks Sofosbuvir + ribavirin 24 weeks 29

30 Genotype 5 - ini1al Sofosbuvir + ribavirin + PEG- IFN 12 weeks Genotype 6 - ini1al Ledipasvir/sofosbuvir (Harvoni) 12 weeks 30

31 Alterna1ve regimens There are addi1onal alterna1ve regimens for genotypes 3, 4, 5, 6 Most contain PEG- IFN Drug interac1ons Direct ac1ng an1virals have important drug interac1ons, including An1retrovirals Acid reducing agents An1convulsants An1microbials azoles, rifamycins, macrolides Calcineurin inhibitors Herbal products Sta1ns 31

32 Cost 12 weeks Sofosbuvir - $84,000 Simeprevir - $66,000 Sofosbuvir/ledipasvir - $94,500 Paritaprevir/ritonavir/ombitasvir + dasabuvir - $83,300 32

33 Hepa11s C take home points Chronic hepa11s C is associated with significant morbidity and mortality Screen those at higher risk of infec1on Treatment should be considered in all pa1ents New, highly effec1ve therapies are here Rapid evolu1on of op1ons Cost is a barrier 33