2013 UPDATES IN HEPATITIS B & C

Transcription

1 2013 UPDATES IN HEPATITIS B & C Jennifer C. Lai, MD, MBA Division of Gastroenterology/Hepatology University of California, San Francisco Financial disclosures: none Outline: HBV & HCV Case-based presentations Recommendations for screening and monitoring disease progression in clinical practice Therapeutic options Identifying candidates for therapy Additional monitoring after therapy 1

2 CASE 1: HBV Case #1: 41 year old Chinese woman HPI: No complaints Here for her 1 st visit to establish primary care with you PMH/PSH: None Meds: Multivitamin SHx: Immigrated from Hong Kong 10 years ago. Works in advertising. Occasional alcohol, no tobacco/ilicits. FHx: Maternal uncle died at age 55 with liver cancer; mother/father/siblings HBV status unknown PE: unremarkable Should she be screened for HBV? A) Yes B) No 2

3 Case #1: 41 year old Chinese woman HPI: No complaints Here for her 1 st visit to establish primary care with you PMH/PSH: None Meds: Multivitamin SHx: Immigrated from Hong Kong 10 years ago. Works in advertising. Occasional alcohol, no tobacco/ilicits. FHx: Maternal uncle died at age 55 with liver cancer; mother/father/siblings HBV status unknown PE: unremarkable Should she be screened for HBV? YES! Who should be screened for HBV? Individuals born in high (8%) or intermediate (2-7%) prevalence areas Asia, Africa, Middle East (except Israel), Spain, Eastern Europe, Central/South America Blood and organ donors Pregnant women Infants of HBsAg+ mothers, household contacts Behavioral contacts: HIV+, MSM, IVDU, inmates Renal dialysis patients Patients receiving immunosuppressive therapy Abnormal ALT of unknown cause Lok, AASLD HBV Practice Guidelines

4 What initial tests should you send to evaluate HBV status in this patient? Option HBsAb HBcAb HBsAg HBV DNA ALT A B C D E F G What initial tests should you send to evaluate HBV status in this patient? Option HBsAb HBcAb HBsAg HBV DNA ALT A B C D E F G 4

5 Interpretation of testing Next steps HBsAb HBcAb HBsAg Interpretation Next Step Not immune Vaccinate + Immune Nothing + + Immune Nothing + Prior exposure/false(+) core Ab + Chronic infection Educate re: risk of reactivation Determine state of infection Case #1: Results from screening HBsAb HBcAb HBsAg Interpretation Next Step Not immune Vaccinate + Immune Nothing + + Immune Nothing + Prior exposure/ False(+) core Ab + Chronic infection Educate re: risk of reactivation Determine state of infection 5

6 Initial approach to HBsAg+ patient 1) Determine stage of fibrosis (i.e., does the patient have cirrhosis?) Platelet count Albumin PT/INR Abdominal ultrasound liver contour, spleen size, main portal vein diameter, recanalized umbilical vein 2) Determine risk factors for accelerated disease HIV/HCV/HDV antibody Heavy alcohol consumption HAV antibody vaccinate if not immune 3) Determine state of infection ALT HBV DNA HBeAg, HBeAb State of infection for chronic (>6 mo) HBV Chronic active HBeAg(+): ALT 1-2x ULN HBeAg(-): HBV DNA>2,000 IU/mL + ALT 1-2x ULN Liver biopsy showing moderate-severe necroinflammation Chronic inactive ( carrier ) HBeAg(-), HBeAb(+) HBV DNA <2,000 IU/mL Persistently normal ALT (<20 for women, <30 for men) Resolved infection HBcAb+ Undetectable HBV DNA Normal ALT (<20 for women, <30 for men) Lok, AASLD HBV Practice Guidelines

7 State of infection for chronic (>6 mo) HBV Chronic active HBeAg(+): ALT 1-2x ULN HBeAg(-): HBV DNA>2,000 IU/mL + ALT 1-2x ULN Liver biopsy showing moderate-severe necroinflammation Chronic inactive ( carrier ) HBeAg(-), HBeAb(+) HBV DNA <2,000 IU/mL Persistently normal ALT (<20 for women, <30 for men) Resolved infection HBcAb(+), HBsAg(-) Undetectable HBV DNA Normal ALT (<20 for women, <30 for men) Refer to hepatology Lok, AASLD HBV Practice Guidelines State of infection for chronic (>6 mo) HBV Chronic active HBeAg(+): ALT 1-2x ULN HBeAg(-): HBV DNA>2,000 IU/mL + ALT 1-2x ULN Liver biopsy showing moderate-severe necroinflammation Chronic inactive ( carrier ) HBeAg(-), HBeAb(+) HBV DNA <2,000 IU/mL Persistently normal ALT (<20 for women, <30 for men) Resolved infection HBcAb+ Undetectable HBV DNA Normal ALT (<20 for women, <30 for men) Refer to hepatology Monitor ALT/HBV DNA Q3mo x 1 yr, then Q6-12 mo Lok, AASLD HBV Practice Guidelines

8 State of infection for chronic (>6 mo) HBV Chronic active HBeAg(+): ALT 1-2x ULN HBeAg(-): HBV DNA>2,000 IU/mL + ALT 1-2x ULN Liver biopsy showing moderate-severe necroinflammation Chronic inactive ( carrier ) HBeAg(-), HBeAb(+) HBV DNA <2,000 IU/mL Persistently normal ALT (<20 for women, <30 for men) Refer to hepatology Monitor ALT/HBV DNA Q3mo x 1 yr, then Q6-12 mo Resolved infection HBcAb+ Undetectable HBV DNA Normal ALT (<20 for women, <30 for men) Consider HBV treatment if immunosuppressed. Lok, AASLD HBV Practice Guidelines Case #1: Lab/Imaging tests Initial work-up: Stage of disease: Platelet count 180, INR 1, Albumin 4.2 Abdominal U/S: Homogeneous liver, no nodularity, normal spleen, main portal vein 8mm, no ascites, no focal hepatic lesions Risk factors for accelerated disease progression: HCV Ab (-), HIV Ab (-), HDV Ab (-), HAV total Ab (+), no heavy alcohol State of infection: HBeAg(-), HBeAb(+) Time ALT HBV DNA Initial 18 U/mL 1,855 IU/mL 8

9 Her state of chronic HBV infection? Time ALT HBV DNA Initial 18 U/mL 1,855 IU/mL Month 3 29 U/mL 1,907 IU/mL Month 6 45 U/mL 4,276 IU/mL Month 9 22 U/mL 3,542 IU/mL A. Chronic active B. Chronic inactive C. Resolved Her state of chronic HBV infection? Time ALT HBV DNA Initial 18 U/mL 1,855 IU/mL Month 3 29 U/mL 1,907 IU/mL Month 6 45 U/mL 4,276 IU/mL Month 9 22 U/mL 3,542 IU/mL A. Chronic active B. Chronic inactive C. Resolved 9

10 You refer her to a hepatologist. HBV treatment is considered but not absolutely indicated. Elevated ALT (>20 U/mL) and HBV (>2,000 U/mL) Uncle with primary liver cancer Age >40 years Initial treatment options for treatment naïve patients: Entecavir (Baraclude) pregnancy category C Tenofovir (Viread) pregnancy category B Patient wants to have a child in the next year and does not want to be on HBV therapy during pregnancy. Liver biopsy shows Stage 2 fibrosis (out of 4) Treatment is deferred until after pregnancy. You refer her to a hepatologist. HBV treatment is considered but not absolutely indicated. Elevated ALT (>20 U/mL) and HBV (>2,000 U/mL) Uncle with primary liver cancer Age >40 years Initial treatment options for treatment naïve patients: Entecavir (Baraclude) pregnancy category C Tenofovir (Viread) pregnancy category B Patient wants to have a child in the next year and does not want to be on HBV therapy during pregnancy. Liver biopsy shows Stage 2 fibrosis (out of 4) Treatment is deferred until after pregnancy. 10

11 HBV and pregnancy/birth HBV DNA should be checked at 28 weeks Initiate tenofovir if HBV DNA >1mill IU/mL (1 billion copies/ml) Goal is to reduce viral load at the time of delivery No indication for C-section vs. vaginal delivery At birth, newborn should receive HBIg and 1 st dose of 3- part HBV vaccine No contraindications to breastfeeding* Except with open sores on nipples Monitor labs 6 weeks after pregnancy (risk of flare) *CDC and WHO. Case #1: 6 weeks after pregnancy Time ALT HBV DNA Initial 18 U/mL 1,855 IU/mL Month 3 29 U/mL 1,907 IU/mL Month 6 45 U/mL 4,276 IU/mL Month 9 22 U/mL 3,542 IU/mL 6 weeks post-partum 125 U/mL 24,000 IU/mL Total bilirubin 1, INR 1 HBeAg(+), HBeAb(-) HBV seroconversion/reactivation Breastfeeding is NOT recommended for mothers on antiviral therapy Monitored for evidence of liver disease progression, then started entecavir at 6 months post-partum when she decided to stop breastfeeding 11

12 Monitoring HBV If on treatment: ALT and HBV DNA every 6 months If on tenofovir: Creatinine and phosphorus every 6 months (Fanconi s syndrome) Dose reductions needed with renal insufficiency for both entecavir and tenofovir If not on treatment: ALT/HBV DNA every 3 mo for the first year Then every 6 months if no indication for treatment HBeAg and HBeAb every year Optional: platelet count, albumin, and INR HBV & Hepatocellular Carcinoma (HCC) HCC screening is recommended in the following groups: Population group Male >40 years Female >50 years Family history of HCC at any age African Cirrhosis Incidence of HCC % per year % per year Higher than without a family history HCC risk is high at any age 3-8% per year Bruix, AASLD HCC practice guidelines

13 How to perform HCC screening? A. AFP every 6 months B. Abdominal ultrasound every 6 months C. AFP + abdominal ultrasound every 6 months D. AFP + abdominal ultrasound every year E. AFP + abdominal ultrasound, but interval depends upon HCC risk in the patient How to perform HCC screening? A. AFP every 6 months B. Abdominal ultrasound every 6 months C. AFP + abdominal ultrasound every 6 months D. AFP + abdominal ultrasound every year E. AFP + abdominal ultrasound, but interval depends upon HCC risk in the patient Bruix, AASLD HCC practice guidelines

14 How to perform HCC screening? A. AFP every 6 months B. Abdominal ultrasound every 6 months C. AFP + abdominal ultrasound every 6 months D. AFP + abdominal ultrasound every year E. AFP + abdominal ultrasound, but interval depends upon HCC risk in the patient HCC screening Official recommendation: Abdominal U/S every 6 months Guidelines do not recommend AFP, but many hepatologists use it 30% of HCC will not produce AFP should not be used alone Sharp rise in AFP may prompt more detailed imaging (CT, MRI) Screening interval is based on HCC doubling time, not on the risk of HCC in the patient Improved survival among HBV infected patients with Q6 month vs. Q12 month screening interval Bruix, AASLD HCC practice guidelines Kim DY, Hepatology

15 HBV: A life-long, dynamic disease All patients from intermediate/high prevalence HBV countries or with behavioral risk factors should be screened Screening labs: HBsAb, HBcAb, HBsAg Initial work-up for HBsAg+ patient: State of infection: ALT, HBV DNA, HBeAg, HBeAb Stage of disease: Platelet, Albumin, INR, Abdominal ultrasound Risk factors for disease progression: HCV, HIV, HDV coinfection Monitor patients not on treatment with: ALT/HBV DNA Q3 months x 1 year, then Q6 months HCC screening with abdominal ultrasound +/- AFP in: Males >40 years, females >50 years, all Africans, HCC fhx, cirrhotics CASE 2: HCV 15

16 Case #2: 54 year old male HPI: No complaints Here for his 1 st visit to establish primary care with you PMH/PSH: Hypertension, depression with one suicide attempt (2001), s/p splenectomy after gun-shot wound (1970) Meds: HCTZ, zoloft SHx: Lives alone, little social support. Remote intranasal cocaine. Drank heavily until daily marijuana use FHx: Father with alcoholism PE: well healed ex-lap scar, palmar erythema, no hepatomegaly, no palpable spleen Should he be screened for HCV? A) Yes B) NoYES! Case #2: 54 year old male HPI: No complaints Here for his 1 st visit to establish primary care with you PMH/PSH: Hypertension, depression with one suicide attempt (2001), s/p splenectomy after gun-shot wound (1970) Meds: HCTZ, zoloft SHx: Lives alone, little social support. Remote intranasal cocaine. Drank heavily until daily marijuana use FHx: Father with alcoholism PE: well healed ex-lap scar, palmar erythema, no hepatomegaly, no palpable spleen Should he be screened for HCV? YES! 16

17 Screening Recommendations Individuals at high risk: IVDU current and past Recipients of clotting factors before 1987 or blood transfusions/organ transplant before July 1992 Patients on chronic hemodialysis Persons with HIV infection Current sexual partners of HCV-infected individuals CDC: All individuals born between (48-68 years old) should be screened USPSTF: Consider birth cohort-based screening CDC MMWR 2012; Chou, Ann Intern Med Total U.S. prevalence of chronic HCV: 1.6%, but strong birth cohort effect Armstrong, Ann Intern Med

18 Total U.S. prevalence of chronic HCV: 1.6%, but strong birth cohort effect IVDU, blood transfusions Armstrong, Ann Intern Med Total U.S. prevalence of chronic HCV: 1.6%, but strong birth cohort effect Time from infection to cirrhosis: yrs 25% have cirrhosis now 45% expected to have cirrhosis in 2020 IVDU, blood transfusions Armstrong, Ann Intern Med

19 Total U.S. prevalence of chronic HCV: 1.6%, but strong birth cohort effect Time from infection to cirrhosis: yrs 25% have cirrhosis now 45% expected to have cirrhosis in 2020! IVDU, blood transfusions Armstrong, Ann Intern Med Case #2: His HCV antibody is positive. Anti-HCV by EIA: 99% specific, but: Approximately 3.6% of the U.S. population has positive anti-hcv but has an undetectable HCV viral load Spontaneous clearance Sustained virologic response (from prior treatment) False positive Next step Check HCV RNA 19

20 Case #2: His HCV RNA is detectable. What should you do next? A. Refer to a hepatologist A. Check HCV viral load and HCV genotype, and refer to a hepatologist B. Check HCV viral load, HCV genotype, platelets, creatinine, liver panel, albumin, PT/INR, and refer to a hepatologist C. Check HCV viral load, HCV genotype, platelets, creatinine, liver panel, albumin, PT/INR, abdominal U/S and refer to a hepatologist Currently Available HCV Treatments Genotype 1a/b Triple-drug therapy for 6-12 months Peg-Interferon (SQ Qwk) + Ribavirin (2-3 pills BID) + Protease Inhibitor (telaprevir/boceprevir) Response rates (those who achieve sustained virologic response): Treatment naïve/relapsers: 75% Null-responders: 50% New! As of June 2011 Genotype 2/3 for 6-12 months Peg-Interferon + Ribavirin Response rates: 80-90% 20

21 But there are multiple costs to treatment US $40-50,000 minimum per treatment course Treatment course: 6-12 months (sometimes 18 months) High pill burden, self-injections Multiple adverse effects Interferon exacerbates underlying psychiatric issues, accelerated CAD or diabetic retinopathy, neutropenia, thrombocytopenia, autoimmune flare, lowers seizure/pain threshold Ribavirin anemia, GI distress, pruritic rash, insomnia Telaprevir rash (severe), DRESS, anal pruritus Boceprevir anemia, headache, nausea Limited tolerability Characteristics of persons for whom therapy is currently contraindicated Major uncontrolled depressive illness Solid organ transplant (renal, heart, lung) Autoimmune hepatitis Untreated thyroid disease Pregnant or unwilling to take contraception Severe concurrent medical disease (e.g., severe HTN, heart failure, poorly controlled diabetes, COPD, severe CAD) that may be exacerbated by treatment or reduce long-term benefit Ghany, Hepatology

22 Characteristics of persons for whom therapy is widely accepted Liver biopsy showing chronic hepatitis with significant fibrosis (Stage 3 of 4 or higher) Compensated cirrhosis Hemoglobin > 13 g/dl for men, >12 g/dl for women Creatinine < 1.5 mg/dl Willing to be treated No contraindications Ghany, Hepatology Characteristics of persons for whom therapy should be individualized Failed prior treatment Current substance abuse, including heavy alcohol Recommend sobriety period of >6 months Liver biopsy with no or mild fibrosis Chronic renal disease Acute hepatitis C or HIV Decompensated cirrhosis Ghany, Hepatology

23 HCV Treatment Horizon: New! Drugs [Direct-Acting Antiviral Agents (DAA)] The all-oral regimens are coming! Mechanism NS3/4A Protease Inhibitors NS5A Inhibitors NS5B Nucleoside Inhibitors NS5B Non-Nucleoside Inhibitors Genotypic coverage Potency High High Intermediate Barrier to resistance Intermediate/high Low/intermediate High Limited Intermediate Low HCV Treatment Horizon: New! Drugs [Direct-Acting Antiviral Agents (DAA)] The all-oral regimens are coming! Mechanism NS3/4A Protease Inhibitors NS5A Inhibitors NS5B Nucleoside Inhibitors NS5B Non-Nucleoside Inhibitors Genotypic coverage Multigenotypic Multigenotypic Pangenotypic Multigenotypic Multigenotypic Pangenotypic Potency High High Intermediate Barrier to resistance Intermediate/high Low/intermediate High Limited Intermediate Low 23

24 So what does this mean for HCV treatment now? Treatment is generally reserved for patients with advanced fibrosis/cirrhosis (without contraindications) Non-invasive evaluation for cirrhosis/portal hypertension Liver biopsy Those with portal hypertension or history of hepatic decompensation should be considered for liver transplant listing prior to HCV treatment initiation Treatment course is 12 months (for cirrhotics) Treatment is less effective for patients with advanced fibrosis/cirrhosis Case #2: Results CBC BMP Liver panel T Bili 1.3 Alk 122 Alb 3.1 AST 57 ALT 20 ALT 68 INR 1.2 Abdominal U/S: Liver shows mild, homogeneous echogenicity c/w fatty infiltration. Main portal vein 14mm. Absent spleen. No ascites. What is his stage of disease? 24

25 Case #2: Results CBC BMP Liver panel T Bili 1.3 Alk 122 Alb 3.1 AST 57 ALT 20 ALT 68 INR 1.2 Abdominal U/S: Liver shows mild, homogeneous echogenicity c/w fatty infiltration. Main portal vein 14mm. Absent spleen. No ascites. What is his stage of disease? Case #2: Results CBC BMP Liver panel T Bili 1.3 Alk 122 Alb 3.1 AST 57 ALT 20 ALT 68 INR 1.2 Abdominal U/S: Liver shows mild, homogeneous echogenicity c/w fatty infiltration. Main portal vein 14mm. Absent spleen. No ascites. What is his stage of disease? 25

26 Case #2: Results CBC BMP Liver panel T Bili 1.3 Alk 122 Alb 3.1 AST 57 ALT 20 ALT 68 INR 1.2 Abdominal U/S: Liver shows mild, homogeneous echogenicity c/w fatty infiltration. Main portal vein 14mm. Absent spleen. No ascites. What is his stage of disease? Case #2: Liver biopsy and management Liver biopsy showed Stage 3-4 (out of 4) disease Although psychiatric symptoms had been stable recently, he was sufficiently concerned about mood-related effects of interferon, so decided to defer treatment for now. 26

27 Patient counseling/monitoring Avoid factors that accelerate fibrosis progression Excess alcohol Obesity, poorly controlled metabolic syndrome factors Daily marijuana If cirrhotic: Advise alcohol abstinence HCC surveillance Avoid sharing needles/razors Use barrier method contraception if not in a monogamous relationship (but sexual transmission is rare) Test for and vaccinate against Hepatitis A and B Ishida, Clin Gastro Hep HCV: Key points Screen all individuals with at high risk for HCV transmission and/or born between (CDC) The % of patients with chronic HCV and cirrhosis is expected to reach 45% by 2020 Screening tests: HCV antibody. If positive: HCV RNA, HCV genotype, liver panel Non-invasive staging: Plt, INR, Alb, complete abdominal U/S Triple-drug therapy is available for genotype 1, but current HCV treatment regimens are burdensome with multiple adverse effects, and still involve interferon HCV treatment is generally reserved for those with advanced fibrosis But new all-oral regimens are expected in early

28 Questions? 28