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)