Chronic HEPATITIS B Infection Diagnosis and Recent management


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1 : Chronic HEPATITIS B Infection Diagnosis and management Dr NEERAJ NAGAICH Dept of gastroenteroloy SMS medical college jaipur.
2 : Three quarters of the world’s 5.2 billion people live in endemic regions Nearly 75% of chronic carriers are Asian. HBV is 100 times more contagious than HIV. A world-wide public health problem
3 : Established cause of chronic hepatitis and cirrhosis. 2nd most important carcinogen behind tobacco. cause of up to 80% of Hepatocellular carcinomas. A world-wide public health problem
4 : Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ?8% - High 2-7% - Intermediate <2% - Low
5 : Hepatitis B Immunopathogenesis
6 : Natural History
7 : Outcome Of Acute Hepatitis B
8 : >90% of Children <5% of Adults Acute HBV Infection Recovery Protective Immunity Transplant or Death Chronic HBV Infection Hepatocellular Carcinoma (HCC) Cirrhosis 30-40% Risk Natural history 10% of Children 95% of Adults
9 : Phases of Infection
10 : Phases of Chronic HBV Infection
11 : ``` wi Whom to screen Patients with elevated liver enzymes Patients with HCC, Cirrhosis ,liver fibrosis Immigrants from areas of high HBV prevalence Families , household members and sexual contacts of HBV + person Patients in psychiatric institutions, residents of welfare institutions and mentally disabled Homo/Bisexuals and person having multiple sexual partners Active and ex drug user Dialysis patients HCV or HIV infected persons
12 : Recipients of organ transplant before and after transplant Blood and organ donors All medical personnel's All pregnant women Patients before and during immunosuppressive or chemotherapy therapy New borne to HBsAg + ve mothers Whom to screen…
13 : Diagnosis
14 : Diagnosis
15 : HBsAg negative antiHBc negative susceptible antiHBs negative HBsAg negative antiHBc positive immune due to natural infection antiHBs positive HBsAg negative antiHBc negative immune due to vaccine antiHBs positive HBsAg positive antiHBc ( total ) positive acutely infected IgM antiHBc positive antiHBs negative HBsAg positive antiHBc ( IgG) positive chronically IgM antiHBc negative infected antiHBs negative HBsAg negative antiHBc ( IgG) positive antiHBs negative Interpretation of Hepatitis B Panel 1.resolution of chronic infection 2. “window period” infection 3. false-positive anti-HBc 4. active infection with waning HBsAg
16 : Treatment
17 : HBV infection cannot eliminated or “cured” The clinical goal of HBV treatment (primary goal ) Prevention or reversal of complications /deaths suppress HBV replication and achieve a target HBV DNA <10-15 IU/mL Can allow biochemical remission and prevent further liver injury Goals of HBV Therapy
18 : In HBeAg-positive patients (cont) HBeAg loss and seroconversion In HBeAg-positive and HBeAg-negative patients HBsAg loss and seroconversion is ultimate form of HBV treatment success Best predictor of durable viral suppression Strongest indicator of best longterm outcome, lowest risk of cirrhosis and liver cancer Not achieved by the majority of patients Histological Improvement Goals of HBV Therapy
19 : Options in treatment
20 : Interferon alfa-2b Lamivudine Adefovir Peginterferon alfa-2a Telbivudine Tenofovir 1990 1998 2002 2005 2006 2008 Entecavir 1990 1998 2002 2005 2006 2008 Evolution of Approved HBV Therapy Over Time
21 : Criteria for HBV DNA, ALT and disease stage/grade must all be met If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242. Recommendations for Treatment Initiation in HBeAg-Positive Patients
22 : Criteria for HBV DNA, ALT and disease stage/grade must all be met If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242. Recommendations for Treatment Initiation in HBeAg-Negative Patients
23 : Regardless of HBV DNA and ALT levels Patients with rapid deterioration of liver function Patients with compensated cirrhosis If DNA > 2,000 IU/mL, regardless of ALT Patients with decompensated cirrhosis (IFN contraindicated) Recurrent HBV infection post liver transplantation HBV carriers undergoing immunosuppressive or cytotoxic chemotherapy Special Populations That Should Also Be Considered for HBV Treatment
24 : Factors Associated With Choosing Nucleos(t)ides as Initial Therapy Favorable predictors of response High ALT Low HBV DNA (baseline and on treatment) Specific patient demographics Older people Patient preference Concomitant HIV infection No HCV coinfection
25 : Selecting Between Recommended First Line Nucleos(t)ide and Interferon Therapy
26 : Selecting a First-line Nucleos(t)ide
27 : Safety Efficacy (potency) Barrier to resistance (durability) Factors Driving Selection of Initial Nucleos(t)ide
28 : Efficacy (Potency)
29 : HBeAg Positive HBeAg Negative Undetectable* HBV DNA (%) 100 80 60 40 20 0 LAM ADV ETV LdT TDF 40-44 13-21 67 60 76 60-73 51-63 90 88 91 100 80 60 40 20 0 LAM ADV ETV LdT TDF Not head-to-head trials; different patient populations and trial designs *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242. Undetectable* HBV DNA in HBV Patients After 1 Year of Treatment
30 : HBeAg Loss HBeAg Seroconversion 100 80 60 40 20 0 LAM ADV ETV LdT TDF 32 24 22 26 22 12-18 21 23 21 100 80 60 40 20 0 LAM ADV ETV LdT TDF NR HBeAg Loss/Seroconversion (%) Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816 Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Not head-to-head trials; different patient populations and trial designs HBeAg Loss/Seroconversion in HBeAg-Positive Patients After 1 Year of Treatment
31 : Lai CL, et al. N Engl J Med. 1998;339:61-68. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al. 2008;359:2442-2455. Normalization of ALT and Histological Improvement After 1 Year of Treatment
32 : Resistance and Treatment Durability
33 : Year 0 24 49 67 70 38 1 2 3 4 5 Patients (%) 80 40 60 20 100 0 3 11 18 29 0.2 1.2 1.2 4 0 0 17 1.2 6 1.2 LAM ADV ETV LdT TDF 0.5 Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients
34 : LAM and LdT Potent agents with low genetic barriers and high rates of resistance ADV Less potent agent with low pharmacologic barrier with intermediate rate of resistance ETV Potent agent with high pharmacologic and genetic barriers and low rates of resistance TDF Potent agent with high pharmacologic and low rates of resistance, genetic barrier not yet defined Summary of Potency and Genetic Barrier to Resistance
35 : Cirrhosis (especially decompensated) High risk of hepatitis flare with emergence of resistance HIV/HBV coinfection Drugs with dual antiviral activity must be used in combination to prevent drug resistance Preexisting resistance Rates of infection with resistant virus low but increasing No data showing benefit of combination therapy vs. monotherapy with newer more potent agents in treatment naïve patients Proposed Special Populations for Combination Therapy
36 : Summary of FDA Approved Oral HBV Treatments *Approximate and relative. †Number of mutations needed for primary antiviral drug resistance. ‡Only includes reported adverse events that may differ in historical incidence associated with LAM and, therefore, potentially affecting selection vs other agents. Pancreatitis has been reported as a class effect and all agents have to be dose adjusted for renal insufficiency. § From HIV databases
37 : Use nucleos(t)ides as monotherapy with Highest antiviral potency and genetic barrier to resistance Low incidence of resistance over time LAM/LdT/ADV not generally recommended as first-line therapy Combination therapy may be considered in patients where avoiding resistance is especially important Consider individual patient characteristics in relation to safety Comorbidities (ie, compromised renal function) Coinfections (ie, anti-HIV activity of agents) Conception planning Summary: Selecting the Best Nucleos(t)ide for Initial Therapy
38 : Tenofovir Disoproxil Fumarate
39 : Tenofovir vs Adefovir comparison of results at week 48
40 : 1 year ADV Fibrosis = 5/6 5 years ADV Fibrosis = 3/6 Patient 1566 (year 5 cohort) Regression of Fibrosis on ADV
41 : Selecting an Interferon-Based Initial HBV Treatment
42 : Favorable predictors of response Genotype A or B > C or D Low HBV DNA (baseline and on treatment) High ALT (baseline) Specific patient demographics Younger people Young woman wanting future pregnancy Patient preference No coinfection with HIV Concomitant HCV infection Factors Associated With Choosing Interferon for Initial Therapy
43 : Months Depression Fatigue Flu-like symptoms Anxiety 1 2 3 4 0 Increase in Incidence/Severity Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Patients should be carefully monitored for adverse events Most common adverse events: flu-like symptoms (fever, chills, headache, malaise, and myalgia) as well as psychological impairment PegIFN Treatment-Associated Adverse Effects
44 : 0 20 40 60 80 100 PegIFN 180 µg (n = 271) PegIFN + LAM (n = 271) LAM 100 mg (n = 272) 27 24 20 HBV DNA < 105 copies/mL (~ 20,000 IU/mL) ALT Normal HBeAg Loss HBeAg Seroconversion 30 27 22 52 86 62 39 46 62 Patients (%) HBV DNA < 400 copies/mL (~ 80 IU/mL) 25 69 40 Peglfa-2a vs LAM vs Combination at EOT (48 Weeks) in HBeAg-Positive Patients HBsAg seroconversion: 0% in all 3 arms Lau GK, et al. N Engl J Med. 2005;352:2682-2695.
45 : HBeAg Seroconversion (%) 32 27 19 0 10 20 30 40 50 PegIFN (n = 271) PegIFN + LAM (n = 271) LAM (n = 272) P < .001 P = .023 60 70 80 90 100 Off-Treatment Follow-up (Week 72) HBeAg Seroconversion After EOT (Week 48)
46 : Years After Therapy Completed Patients with HBV DNA = 400 copies/mL (%)* 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 13 13 18 17 Viral Suppression in HBeAg-Negative Patients After PegIFN-2a ± LAM Treatment *~ 80 IU/mL, missing data considered a nonresponse. Marcellin P, et al. AASLD 2006. Abstract. 972. Marcellin P, et al. EASL 2007. Abstract 53. Marcellin P, et al. EASL 2008. Abstract 103.
47 : HBsAg decrease at Week 12 associated with subsequent sustained treatment response in both HBeAg-positive or HBeAg-negative patients Suggests that HBsAg monitoring could be beneficial in identifying Patients likely to respond favorably in the long term Patients likely to be nonresponders Who might benefit from an alternative treatment approach Lau GK, et al. APASL 2009. Abstract PE083. Moucari R, et al. Hepatology. 2009;49:1151-1157. Brunetto MR, et al. Hepatology. 2009;49:1411-1150. Moucari R, et al. J Hepatol. 2009;50:1084-1092. Perillo RP. Hepatology. 2009;49:1063-1065. Early HBsAg Kinetics Are Predictive of Long-term PegIFN Treatment Success
48 : Advantages: finite duration of treatment, durable response in a subset of responding patients; lack of viral resistance development Disadvantages: administered by subcutaneous injections; associated with significant toxicities in most patients HBeAg and HBsAg seroconversion rates, tolerability, and likelihood of response to treatment vs nucleos(t)ides all play a role decision HBsAg kinetics may offer a early idea of the likelihood of response Summary of PegIFN alfa-2a as Initial Therapy
49 : Other Factors to Consider When Initiating First-line Treatment
50 : Women with mild liver disease, low viremia Pregnancy before treatment Women with moderate liver disease, no cirrhosis Treatment before pregnancy; if response, stop treatment before pregnancy Women with advanced liver disease Treatment before and during pregnancy; continue treatment after delivery Women with mild liver disease, very high viremia Treatment in last trimester with “B” category drug Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782. EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Recommendations for HBV-Infected Women Who Desire Pregnancy
51 : Dialysis and Renal Transplantation Patients ADV and TDF have been linked to worsening renal function and should be used with caution in renally impaired patients No specific renal toxicity associated with entecavir Dose-adaptation should be used with any agent TDF can be used if dose adjustments are made in response to changes in GFR Monitoring of renal function before and during therapy particularly important.
52 : post-exposure prophylaxis
53 : Test exposed person No treatment Test exposed person for anti-HBs for anti-HBs 1. If adequate, no 1. If adequate, no treatment is treatment is necessary. necessary. 2. If inadequate*, 2. If inadequate*, administer administer vaccine HBIG x 1 and booster and vaccine booster. recheck titer in 1-2 months. Antibody response unknown HBIG X 1 and initiate No treatment If known high risk revaccination source, treat as or HBIG X 2 if source were HBsAg positive Known non-responder* Source HBsAg +ev No treatment No treatment No treatment Known responder Previously vaccinated HBIG x 1 and initiate Initiate HB vaccine Initiate HB vaccine HB vaccine series series series Unvaccinated Treatment Vaccination and antibody response status of exposed workers Recommended post-exposure prophylaxis for exposure to HBV Source: MMWR, June 29 2001, vol 50, RR-11, p22 * A non-responder is a person with inadequate levels of serum antibody to HBsAg (I.e., anti-HBs <10 mIU/mL). Source HBsAg -ve Source unknown
54 : Take home message Suspect and Diagnose. Initial evaluation includes education Family and contacts should be tested Monitor as status changes over time Selection of patients to treat Individualize treatment decisions Change if no/ poor response Long term monitoring HCC, special populations, reactivation.
55 : Prevention is better than cure. Take home message
56 : THANK YOU
57 :
58 : Outcomes of chronic Hepatitis B infection
59 : A liver biopsy is indicated in the following scenarios: ? HBeAg-negative and HBV DNA = 20,000 IU/ml and ALT < 2x ULN ? HBeAg-negative and HBV DNA = 2,000–19,999 IU/ml ? HBeAg-positive and HBV DNA = 20,000 IU/ml and ALT < 2x ULN and age = 40
60 : Comparison of the drugs used in treatment-naive patients with chronic hepatitis B Cost /Y 41,400 1,09500 73,000 36,500 100 100
61 : Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy. Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml at 24 weeks of therapy. Serological response is defined by HBe eroconversion in patients with HBeAg-positive CHB. On interferon alpha therapy:
62 : On NUC therapy: Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy. Virological response is defined as undetectable HBV DNA by real-time PCR assay within 48 weeks of therapy. Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA by real-time PCR assay.
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