ChronicChronic HEPATITIS B Infection HEPATITIS B Infection Diagnosis and managementDiagnosis and management

Dr NEERAJ NAGAICHDept of gastroenteroloySMS medical college jaipur.

• 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

• 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

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence

8% - High

2-7% - Intermediate

<2% - Low

Hepatitis B Immunopathogenesis

Natural History Natural History

Outcome Of Acute Hepatitis B

>90% of Children

<5% of Adults

Acute HBV Infection

RecoveryProtective Immunity

Transplant or Death

Chronic HBV Infection

HepatocellularCarcinoma (HCC)

Cirrhosis

30-40% Risk

Natural history

10% of Children

95% of Adults

Phases of InfectionPhases of Infection

Phases of Chronic HBV Infection

``` wiWhom to screen 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

• 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… Whom to screen…

Diagnosis

Diagnosis

HBsAg negative

antiHBc negative susceptible

antiHBs negative

HBsAg negativeantiHBc positive immune due to natural infectionantiHBs positive

HBsAg negativeantiHBc negative immune due to vaccineantiHBs positive

HBsAg positiveantiHBc ( total ) positive acutely infectedIgM antiHBc positiveantiHBs negative

HBsAg positiveantiHBc ( IgG) positive chronicallyIgM antiHBc negative infectedantiHBs negativeHBsAg negativeantiHBc ( IgG) positiveantiHBs negative

Interpretation of Hepatitis B Panel

1.resolution of chronic infection2. “window period” infection3. false-positive anti-HBc4. active infection with waning HBsAg

Treatment Treatment

•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

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 cancerNot achieved by the majority of patients

Histological Improvement

Goals of HBV Therapy

Options in treatmentOptions in treatment

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

AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000

ALT, x ULN* > 2 > 1 > 1

Disease stage/gradeModerate/severe necroinflammation

and/or significant fibrosis

First-line therapyADV,† ETV,

pegIFN ETV, TDF,

pegIFNETV, TDF,

pegIFN

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

AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000

ALT, x ULN* 1 to > 2 > 1 > 1

Disease stage/gradeModerate/severe necroinflammation

and/or significant fibrosis

First-line therapyADV,† ETV,

pegIFN ETV, TDF,

pegIFNETV, TDF,

pegIFN

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

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

Factors Associated With Choosing Nucleos(t)ides as Initial Therapy

Favorable predictors of responseHigh ALT Low HBV DNA (baseline and on treatment)

Specific patient demographicsOlder people

Patient preferenceConcomitant HIV infectionNo HCV coinfection

Nucleos(t)ides Interferon-Based TherapyFeature Pro Con Pro Con

Administration OralLong term/ indefinite

Finite duration Subcutaneous

Antiviral activity HighLow durable rates DNA suppression

ResistanceVery low

resistance† No

Adverse events MinimalRare renal tox with nucleotide

Substantial*

HBeAg loss and clearance

HBeAg loss over time

Lower rates vs. IFN

Higher rates vs nucles(t)ides

HBeAg loss ≠ HBV DNA suppression

HBsAg loss and clearance

Higher and earlier events† Low rates

High rates (select populations)

Low rates in general patient groups

Other Anti HIV (TDF)May induce HIV

resistance (TDF/ETV)

Anti HCV/HDV

Selecting Between Recommended First Line Nucleos(t)ide and Interferon Therapy

Selecting a First-line Nucleos(t)ideSelecting a First-line Nucleos(t)ide

Safety

Efficacy(potency)

Barrier to resistance (durability)

Factors Driving Selection of Initial Nucleos(t)ide

Efficacy (Potency)Efficacy (Potency)

HBeAg Positive HBeAg Negative

Und

etec

tabl

e* H

BV D

NA

(%) 100

80

60

40

20

0LAM ADV ETV LdT TDF

40-44

13-21

6760

76

60-73

51-63

90 88 91100

80

60

40

20

0LAM 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

HBeAg Loss HBeAg Seroconversion100

80

60

40

20

0LAM ADV ETV LdT TDF

3224 22 26 22

12-1821 23 21

100

80

60

40

20

0LAM ADV ETV LdT TDF

NR

HBe

Ag L

oss/

Sero

conv

ersi

on (%

)

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

HBeAg Positive

Outcome, % LAM ADV ETV LdT TDF

Normalization of ALT 41-75 48 68 77 69

Histological improvement 49-56 53 72 65 74

HBeAg Negative

Outcome, % LAM ADV ETV LdT TDF

Normalization of ALT 60-79 72 78 74 77

Histological improvement 60-66 64 70 67 72

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

Resistance and Resistance and Treatment DurabilityTreatment Durability

Year

0

24

49

67 70

38

1 2 3 4 5

Patie

nts

(%)

80

40

60

20

100

03

1118

29

0.2 1.2 1.24

00

171.2

6

1.2

LAM ADV ETV LdT TDF

0.5

Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients

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

ETVPotent 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

Cirrhosis (especially decompensated)High risk of hepatitis flare with emergence of resistance

HIV/HBV coinfectionDrugs 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

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

• 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

Tenofovir Disoproxil Fumarate

HBeAg +ve HB e Ag –ve

Tenofovir 300 mg

176 patients

Adefovir 10 mg

90 patient

Tenofovir 300 mg

250 Patient s

Adefovir 10 mg

125 patients

HBV DNA <400 copies /ml

76% 13% 93% 63%

ALT Normalization

68% 54% 76% 77%

HBeAg Seroconversion

21 18 -- --

Histological Response ≥ 2 log fall KS

74 68 72 69

Tenofovir vs Adefovir comparison of results at week 48

1 year ADVFibrosis = 5/6

5 years ADVFibrosis = 3/6

Patient 1566 (year 5 cohort)

Regression of Fibrosis on ADV

Selecting an Interferon-Based Initial Selecting an Interferon-Based Initial HBV TreatmentHBV Treatment

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

Months

Depression

Fatigue

Flu-like symptoms

Anxiety

1 2 3 40

Incr

ease

in

Inci

denc

e/Se

verit

y

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Patients should be carefully monitored for adverse eventsMost common adverse events: flu-like symptoms (fever, chills,

headache, malaise, and myalgia) as well as psychological impairment

PegIFN Treatment-Associated Adverse Effects

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)

ALTNormal

HBeAgLoss

HBeAgSeroconversion

30 27 22

52

86

62

3946

62

Patie

nts

(%)

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.

HBe

Ag S

eroc

onve

rsio

n (%

)

3227

19

01020304050

PegIFN(n = 271)

PegIFN + LAM(n = 271)

LAM(n = 272)

P < .001P = .023

60708090

100

Off-Treatment Follow-up (Week 72)

HBeAg Seroconversion After EOT (Week 48)

Years After Therapy Completed

Patie

nts

with

HBV

DN

A ≤

400

copi

es/m

L (%

)*

100908070605040302010

01 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.

•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.

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

•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

Other Factors to Consider When Other Factors to Consider When Initiating First-line TreatmentInitiating First-line Treatment

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 drugWedemeyer 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

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.

post-exposure prophylaxis post-exposure prophylaxis

Test exposed person No treatment Test exposed personfor 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 riskrevaccination source, treat asor 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 vaccineHB vaccine series series seriesUnvaccinated

TreatmentVaccination and antibody response status of exposed workers

Recommended post-exposure prophylaxis Recommended post-exposure prophylaxis for exposure to HBVfor 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

Take home message

• Suspect and Diagnose.

• Initial evaluation includes educationo Family and contacts should be tested

• Monitor as status changes over time

• Selection of patients to treato Individualize treatment decisionso Change if no/ poor response

• Long term monitoringo HCC, special populations, reactivation.

Prevention is better than cure.

Take home message

THANK YOU

Outcomes of chronic Hepatitis B infection

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

Comparison of the drugs used in treatment-naive patients with chronic hepatitis B

Cost /Y 41,4001,0950073,00036,500

100 100

Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level frombaseline at 3 months of therapy.

Virological response is defined as an HBV DNAconcentration of less than 2000 IU/ml at 24 weeksof therapy.

Serological response is defined by HBe eroconversionin patients with HBeAg-positive CHB.

On interferon alpha therapy:

On NUC therapy:

Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level frombaseline at 3 months of therapy.

Virological response is defined as undetectableHBV DNA by real-time PCR assay within 48weeks of therapy.

Partial virological response is defined as a decreasein HBV DNA of more than 1 log10 IU/ml butdetectable HBV DNA by real-time PCR assay.

Monitor HBV patients who are not in treatment.

HBeAg(+) and treatment not indicated:

ALT every 3–6 months if WNL; ALT every 1–3 months if 1–2x ULN. HBV DNA viral load every 6–12 months. Liver biopsy if ALT ≥ 2x ULN for 6 months, or if ALT 1–2x ULN for 6 months and age ≥ 40

.

HBeAg(–) and treatment not indicated:

ALT every 3 months for 1 year; then every 6–12 months. HBV DNA viral load if ALT > 1–2x ULN. Liver biopsy if persistent ALT elevation or HBV DNA ≥ 2,000 IU/ml.

.

Monitoring schedule for Nucleos(t)ide Analogues:

ALT and AST levels every 3–6 months

HBeAg every 3–6 months (in patients who are HBeAg(+) at start of treatment)

HBsAg every 6–12 months (in patients who are HBeAg(–) at start of treatment)

HBV DNA viral load every 3 months during first year of therapy; then every 6 months

Serum creatinine every 12 weeks while taking adefovir or tenofovir

Monitoring schedule for Interferon alfa:

Monitor patients on treatment

HCV co-infected patients

HBV DNA level is often low or is undetectable and HCV is responsible for the activity of chronic hepatitis in most patients.

patients should receive pegylated interferon alpha withribavirin as for HCV .

SVR rates for HCV are broadly comparable with HCV monoinfected patients .

potential risk of HBV reactivation during or after clearance of HCV that must then be treated with NUCs

HIV co-infected patients

HIV-positive patients with CHB are at increased riskof cirrhosis . Treatment of HIV may lead to flaresof hepatitis B due to immune restitution.

The indications for therapy are the same as in HIV-negative patients,

it is recommended that most coinfected patients besimultaneously treated for both HIV and HBV de novo.

Tenofovir and emtricitabine (FTC) together, plusa third agent active against HIV, are indicated.

Acute severe hepatitis

95–99% of adults with acute HBV infection will recover spontaneously and seroconvert to anti- HBs without anti-viral therapy.

Some patients with fulminant hepatitis or severe protractedsubacute hepatic necrosis may benefit from NUC treatment.

potent drugs with a high barrier to resistance, i.e. entecaviror tenofovir, should be used.

The duration of treatment is not established. (at least 3 months after seroconversion to anti-HBs or at least 6 months after Hbe Seroconversion is recommended)