CCO Gish Virologic Tools HBV Download Able

Bringing Into Focus: A Practical Guide to Using Virologic and Serologic Tests in the Management of Hepatitis B
Robert G. Gish, MD
Chief of Hepatology Professor of Medicine Division of Gastroenterology Department of Medicine, Liver Transplant University of California, San Diego San Diego, California
This program is supported by educational grants from
Using Virologic and Serologic Tests in the Management of Hepatitis B

clinicaloptions.com/hepatitis
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Faculty Disclosures
Robert G. Gish, MD, has disclosed that he has received grants for research support from Astellas/OSI, Bayer-Onyx, Bristol-Myers Squibb, Chugai, Genentech/Hoffmann-La Roche, Gilead Sciences, Pharmasset, Vertex, and Zymogenetics; has served as a consultant for Abbott, Astellas/OSI, Bayer AG, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Durect, Dynavax, Eiger, Fraxon, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Hepahope, Pharmasset, Somalutions, ZymoGenetics; has served on speaker bureaus for Bayer, Bristol-Myers Squibb, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, Merck, Onyx, and Salix; and owns stock in and serves on the board of directors for Hepahope.
Albert D. Min, MD, has disclosed that he has received grants for research support from Bristol-Myers Squibb, Genentech, Gilead Sciences, and Roche; has served as a consultant for Bristol-Myers Squibb and Gilead Sciences; and has received fees for non-CME services from Bristol-Myers Squibb and Gilead Sciences.
HBV Epidemiology

Geographic Distribution of Chronic HBV Infection
7.2%
HBsAg Prevalence 8% (high) 2% to 7% (intermediate) < 2% (low)
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. Liang X, Bi S, et al. Vaccine. 2009;27:6550-6557.

The HBV Iceberg

Clinical populations are the tip of the iceberg
Individuals in treatment are the tip of the tip
2 million individuals in the US have chronic HBV infection

50,000 receive treatment
150,000 are diagnosed in care and meet treatment guidelines
300,000 are diagnosed in care
500,000 are potentially eligible for treatment 600,000 are aware of their chronic HBV infection
Population-based studies allow us to look at the whole iceberg

Asia has been the place for these
1.4 million are unaware of their chronic HBV infection
Cohen C, et al. J Viral Hepatitis. 2011;18:377-383. Graphic reproduced with permission.

Groups at High Risk for HBV Infection Who Should Be Screened

Persons born in geographic regions with HBsAg prevalence of 2% US-born persons, not vaccinated as infants, whose parents were born in geographic regions with HBsAg prevalence of 8% Persons with chronically elevated aminotransferases Persons needing immunosuppressive therapy
Men who have sex with men

Persons with multiple sexual partners or history of sexually transmitted disease Inmates of correctional facilities Persons who have ever used injection drugs
Dialysis patients
HIV- or HCV-infected individuals Pregnant women Family members, household members, and sexual contacts of HBV-infected persons
Lok AS, et al. Hepatology. 2009;50:661-662.
Initial Evaluation and Tests to Diagnose HBV

Assessing Patient History and Current Presentation

Age
Duration of disease Family history of HCC
Alcohol use
Smoking history Fatty liver disease, diabetes mellitus, metabolic syndrome
Patient motivation, compliance, adherence

Comorbidities: renal, bone Cost of testing and treatment/insurance

Hepatitis B Serology: First Phase Testing

AASLD guidelines recommend HBsAg and anti-HBs testing for all patients
HBsAg
Protein on surface of HBV detected during acute or chronic HBV infection Presence indicates an individual is INFECTED OR INFECTIOUS
Anti-HBs
Presence indicates recovery and IMMUNITY from HBV infection Also develops following vaccination against hepatitis B
Total anti-HBc can be used as alternative; those testing positive should be tested for HBsAg and anti-HBs
Appears at the onset of symptoms in acute hepatitis and persists for life Presence indicates EXPOSURE (previous or ongoing infection with HBV)

Why Do We Need to Do Anti-HBc Testing?

Decide who needs
HBV vaccine
Patients testing negative for HBsAg but positive for anti-HBc in regions of high HBV prevalence have had exposure due to natural infection; therefore, no need to vaccinate*
Chemoprophylaxis for HBV reactivation

Immunocompromised patients can experience reactivation of HBV if anti-HBc is positive
Assess risk of donor HBV transmission

Recipients of livers from anti-HBcpositive patients are at risk for HBV transmission
*However, one of the possibilities for isolated HBcAb (total) is the possibility of false positive in low prevalence areas or in individuals with no risk factors for HBV, in which case they may need to be vaccinated.

Hepatitis B Serology: IgM anti-HBc

IgM anti-HBc (IgM antibody to hepatitis B core antigen)[1]
If you see this test (+/-) on a lab panel
Necessary to test for past HBV exposure; reorder anti-HBc total
Presence indicates acute infection (negative in chronic infection)

Positivity indicates recent infection with HBV ( 6 mos)
Occasionally occurs in the presence of a severe flare of chronic HBV disease

Small minority of pts with chronic HBV are IgM anti-HBc+, indicating higher risk for progression to cirrhosis or HCC[2]
1. CDC. Hepatitis B FAQs for health professionals. Available at: http://www.cdc.gov/hepatitis/ HBV/HBVfaq.htm. 2. Colloredo MG, et al. Arch Virol Suppl. 1993;8:203-211.

Interpretation of Serologic Results

HBsAg Negative Negative Negative Positive Positive Negative Total Anti-HBc Negative Positive Negative Positive Positive Positive IgM Anti-HBc NA NA NA Negative Positive NA Anti-HBs Negative Positive Positive Negative Negative Negative Interpretation Susceptible; offer vaccination Immune due to natural infection Immune due to hepatitis B vaccination Chronic HBV infection Acute HBV infection Unclear; could be any one of the following: 1. Resolved infection (most common) 2. False-positive anti-HBc; susceptible 3. Low-level chronic infection 4. Resolving acute infection
CDC. Hepatitis B FAQs for health professionals. Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm.

Initial Testing in Patients Diagnosed With Chronic HBV

Testing for Patients Who Are HBsAg Positive[1] Lab tests to assess liver disease: CBC, hepatic panel, and INR (prothrombin time) Tests for HBV replication: HBeAg/anti-HBe, HBV DNA Tests to rule out viral coinfections: anti-HCV, anti-HDV (in persons from countries where HDV infection is common and in those with history of injection drug use), and anti-HIV in those at risk
Tests for screening and surveillance for HCC: AFP and ultrasound as appropriate
Consider liver biopsy to grade and stage liver disease: for patients who meet criteria for chronic hepatitis Consider core and precore assays and testing for HBV genotype CDC guidelines recommend HIV testing in ALL chronic HBV patients[2]
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Hepatitis B Serology: Determining HBeAg Status in CHB Patients

HBeAg
Secreted coproduct of nucleocapsid gene of HBV found in serum during acute and chronic HBV with wild-type infection Presence indicates replicating natural variant virus and often associated with high HBV DNA levels
Anti-HBe
Produced by immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication in setting of wild-type infection clearance Conversion from HBeAg positive to anti-HBe positive a predictor of
Long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV
or Emergence of precore, mixed, or core promoter mutant infection and transition to HBeAg-negative disease

HBV Variants
Wild type
Unmutated HBeAg-positive hepatitis Mixed infection with
Basal core promoter mutations (44% of US patients)[1,2] Precore mutations (27% of US patients)[2]
Precore and core promoter mutations[3]

Eventually abolishes HBeAg production (HBeAg-negative CHB)
Genotypes Treatment-induced mutations

1. Buckwold VE, et al. J Virol. 1996;70:5845-5851. 2. Chu CJ, et al. Gastroenterology. 2003;125:444-451. 3. Hunt CM, et al. Hepatology. 2000; 31:1037-1044.

Natural History of HBV Infection

Childhood
> 95%
Immune tolerance
Adulthood
< 5%
HBeAg+ CHB
HBeAg- CHB
Inactive carrier
Cirrhosis
Chen DS, et al. J Gastroenterol Hepatol. 1993;8:470-475. Seeff L, et al. N Engl J Med. 1987;316:965-970.

High Risk of Cirrhosis in Asians & Patients With Vertically Transmitted Disease
The lifetime risk of cirrhosis or cancer in a person who is HBsAg positive is 20% to 30%
Risk is lower for women Risk is highest for men
Fattovich G, et al. Am J Gastroenterol. 2002;97:2886-2895. Fattovich G, et al. Gastroenterology. 2004;11;27:S35-S50. McMahin BJ. Hepatology. 2009;49:S45-S55.

HBV Classified Into 10 Genotypes

Genotype A B and C D E F G H I J Geographic distribution North America, northern Europe, India, and Africa Asia Southern Europe, Middle East, and India West Africa and South Africa Central and South America United States and Europe Central America and California Vietnam Japan
Fung SK, et al. 2004;40:790-792. Norder H, et al. Intervirology. 2004;47:289-309. Tuan Huy TT, et al. J Virol. 2008;82:5657-5663. Tatematsu K, et al. J Virol. 2009;83:10538-10547.

Why Test for HBV Genotype?

Differences in natural history and treatment responsiveness
B is associated with less active disease, slower progression, and lower incidence of HCC than C
C has higher risk of HCC and cirrhosis

A and B respond better to IFN than C and D F is associated with fulminant liver disease; rare
Current guidelines indicate that additional data are needed before testing for genotypes in clinical practice is recommended
Lok AS, et al. Hepatology. 2009;50:661-662. EASL. J Hepatol. 2009;50:227-242.

Summary: Tests for Initial Evaluation and Diagnosis of HBV

Clinical assessment for HBV disease is a multistep process
History Physical exam Serologic tests Nucleic acid tests Liver biochemistries including liver synthetic tests HCC biomarkers Imaging
Tests to Determine Treatment Candidacy

Parameters Used to Determine Candidates for Treatment of HBV

ALT
New normal or healthy ALT: < 30 U/L for men and < 19 U/L for women[1] Presence of 1 normal value does not exclude significant disease or subsequent complications
HBV DNA
Predicts development of cirrhosis and HCC[2,3] Interpret in conjunction with ALT and/or histology
Liver biopsy
Useful in situations where ALT or HBV DNA do not provide clear guidelines for treatment[1]
1. Lok AS et al. Hepatology. 2009;50:661-662. 2. Iloeje UH et al. Gastroenterology. 2006;130:678-686. 3. Chen CJ et al. JAMA. 2006;295:65-73.

Transmission of HBV Is Proportional to HBV DNA Level

Horizontal Transmission Higher DNA, higher risk Infected person Child to child Contaminated needles Sexual Healthcare worker Transfusion Hemodialysis No clear risk factors in 20% to 30% of patients Common in regions with HBsAg prevalence of > 2% Infant Recipient Vertical Transmission
Mother > 106-8 IU/mL Perinatal
CDC. Hepatitis B Information for the Public. Fact sheet. http://www.cdc.gov/hepatitis/B/PatientEduB.htm. Lee WM. N Engl J Med. 1997;337:1733-1745. Lavanchy D. J Viral Hepat. 2004;11:97-107.

Natural History of HBV: Directly Related to HBV DNA Level

Liver cancer (HCC) 5% to 10%
Chronic infection
30%
10% to 15% in 5 yrs Cirrhosis 23% in 5 yrs Liver transplantation* Death
Acute flare
Liver failure
*HBV is the 6th leading cause of liver transplantation in the United States. Fattovich G, et al. Gastroenterology. 2004;127:S35-S50. Seeff LB, et al. Hepatology. 2001;33:455-463. Torresi J, et al. Gastroenterology. 2000;118:S83-S103. Fattovich G, et al. Hepatology. 1995;21:77-82.

Treatment Criteria for Chronic Hepatitis B: Comparison of Guidelines

Guidelines HBeAg Positive
HBV DNA, IU/mL ALT
HBeAg Negative
HBV DNA, IU/mL ALT
EASL 2009[1]
APASL 2008[2] AASLD 2009[3] NIH Consensus Conference 2009[4] US Algorithm 2008[5]
> 2000
20,000 > 20,000 > 20,000 20,000
> ULN
> 2 x ULN > 2 x ULN or positive biopsy > 2 x ULN or positive biopsy > ULN or positive biopsy
> 2000
2000 20,000 20,000 2000
> ULN
> 2 x ULN 2 x ULN or positive biopsy 2 x ULN or positive biopsy > ULN or positive biopsy
1. EASL. J Hepatol. 2009;50:227-242. 2. Liaw YF, et al. Hepatol Int. 2008;3:263-283. 3. Lok AS, et al. Hepatology. 2009;50:661-662. 4. Degerekin B, et al. Hepatology. 2009;S129-S137. 5. Keefe EB. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Clinical Profiles of Chronic HBV Infection

Parameter Immune Tolerance Immune Active/ HBeAg-Positive CHB
200,000 - 2 x 109 Positive
Nonreplicative (Inactive Carrier)

< 2000 Negative Normal HBsAg may become undetectable
HBeAgNegative CHB
2000 - 2 x 107 Negative
Typical HBV DNA, IU/mL HBeAg ALT Other observations Treatment candidate?
> 200,000 Positive Normal Liver biopsy typically normal or minimal findings
Elevated or fluctuating
Active inflammation on liver biopsy
Elevated or fluctuating
Active inflammation on liver biopsy
No
Yes
No
Yes

More Detailed Interpretation of HBV Serologies

HBV Status HBsAg eAg-positive CHB eAg-negative CHB Immune tolerant Inactive carrier Acute hepatitis B Recovered Vaccinated Low-level carrier None + + + + + AntiHBs + + AntiHBc + + + + + + Serologic Marker IgM anti-HBc + HBeAg + + AntiHBe + + HBV DNA, IU/mL > 20,000 > 2000 > 20,000 < 2000 Variable Undetectable Undetectable Detectable or undetectable N/A ALT Elevated Elevated Normal Normal Elevated Normal Normal Yes Yes No No No No No Only with chemo or immunosuppression Vaccinate Treat?
Normal
Normal
EASL. J Hepatol. 2009;50:227-242. Lok AS, et al. Hepatology. 2009;50:661-662.

Noninvasive Serum-Based Tests for Detection of Fibrosis

Test
FibroTest FibroSpect II FibroSURE APRI Forns fibrosis index FIB-4 HepaScore Fibrometer
Parameters Measured
2-macroglobulin, haptoglobin, GGT, total bilirubin, and apolipoprotein A1 2-macroglobulin, hyaluronic acid, and tissue inhibitor of metalloproteinase-1 2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, total cholesterol, triglycerides, and fasting glucose AST-to-platelets ratio index Age, platelet count, GGT, cholesterol Platelets, ALT, AST, and age 2-macroglobulin, GGT, hyaluronic acid, and total bilirubin Age, sex, 2-macroglobulin, hyaluronic acid, platelets, prothrombin index, AST, and urea
No guidelines currently recommend routine clinical use of noninvasive methods for the detection of fibrosis

Transient Elastography: A Potential Noninvasive Alternative to Liver Biopsy

Elastography
Ultrasound transducer probe induces elastic wave through the liver Velocity of the wave is evaluated in a region located from 2.5-6.5 cm below the skin surface Whereas a liver biopsy is able to examine 1/50,000 of the liver, elastography is able to examine 1/500 of the liver
Despite extensive research and progress, no guidelines recommend transient elastography as alternative to liver biopsy for CHB Effective at discriminating between severe and mild fibrosis but less effective at distinguishing intermediate levels of fibrosis[1-2] MRI and MR spectroscopy other potential noninvasive tests to detect cirrhosis[3]
1. Chan HL, et al. J Viral Hepat. 2009;16:36-44. 2. Marcellin P, et al. Liver Int. 2009;29:242-247. 3. Friedrich-Rust M, et al. J Clin Gastroenterol. 2010;44:58-65.

Transient Elastography: Proposed Algorithm for CHB Pts With Normal ALT
Normal ALT
5.0 kPa 91% sensitivity to exclude fibrosis
> 5.0-6.0 kPa 93% sensitivity to exclude bridging fibrosis
> 6.0-9.0 kPa Grey zone
> 9.0-12.0 kPa 100% specificity to diagnose bridging fibrosis
> 12.0 kPa 95% specificity to diagnose cirrhosis
Reassurance
Observe
Liver biopsy
Consider treatment
Consider treatment
Chan HL, et al. J Viral Hepat. 2009;16:36-44.

Transient Elastography: Proposed Algorithm for CHB Pts With Elevated ALT
Elevated ALT (> 1-5 x ULN)
5.0 kPa 92% sensitivity to exclude fibrosis
> 5.0-7.5 kPa 96% sensitivity to exclude bridging fibrosis
> 7.5-12.0 kPa Grey zone
> 12.0-13.4 kPa 98% specificity to diagnosis
> 13.4 kPa 93% specificity to diagnosis cirrhosis
Reassurance
Observe
Liver biopsy
Consider treatment
Consider treatment
Chan HL, et al. J Viral Hepat. 2009;16:36-44.

Summary: Tests for Determining Treatment Candidacy for HBV

Determining treatment candidacy at its most basic is a simple 2-step process of measuring
HBV DNA ALT
However, often important to consider other parameters to individualize treatment

HBV DNA and ALT assessment Coinfection assessment Alcohol or metabolic syndrome AFP
Family history of HCC

Precore, core, and genotype Liver biopsy or advanced imaging for fibrosis
Monitoring a Patient Who Is CHB Positive but Not in Need of Treatment

Patients With Normal ALT May Have Significant Liver Disease

In prospective study of 305 HBsAg-positive patients with persistently normal ALT levels for 1 yr, fibrosis stage 2 observed in[1]
40% of HBeAg-positive patients (n = 189) 14% of HBeAg-negative patients (n = 116)
37% of patients with chronic HBV infection and persistently normal ALT had significant fibrosis (stage 2-4) or inflammation (grade 2-3) by liver biopsy[2]
In large cohort (> 140,000 Koreans), ALT 20 IU/L associated with increased risk of death from chronic liver disease in men during 8 yrs of follow-up[3]
1. Kumar M, et al. Gastroenterology. 2008;134:1376-1384. 2. Lai M, et al. J Hepatol. 2007;47:760-767. 3. Kim HC, et al. BMJ. 2004;328:983.

Monitoring of Patients Not Considered for Therapy

Disease State HBeAg positive HBV DNA > 20,000 IU/mL Normal ALT Recommended Follow-up ALT every 3-6 mos, more often if ALT becomes elevated If ALT levels between 1-2 x ULN, recheck ALT every 1-3 mos; consider liver biopsy if older than 40 yrs of age, ALT borderline or mildly elevated on serial tests; consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis If ALT > 2 x ULN for 3-6 mos and HBeAg positive, HBV DNA > 20,000 IU/mL, consider liver biopsy and treatment Consider screening for HCC in relevant population

Monitoring of Patients Not Considered for Therapy

Disease State Inactive HBsAg carrier state Recommended Follow-up ALT every 3 mos for 1 yr; if persistently normal, ALT every 6-12 mos If ALT > 1-2 x ULN, check serum HBV DNA level and exclude other causes of liver disease; consider liver biopsy if ALT borderline or mildly elevated on serial tests or if HBV DNA persistently 2000 IU/mL; consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis Consider screening for HCC in relevant population

Risk of HCC in Chinese HBV Carriers

Prospective follow-up of 22,707 Taiwanese male civil servants
3454 HBsAg positive (15.2%)
Incidence of HCC higher among HBsAg-positive patients (n = 3454) vs HBsAg-negative patients during 75,000 man-yrs of follow-up
1158/100,000 vs 5/100,000 Relative risk: 223
HCC and cirrhosis accounted for 54.3% of 105 deaths among HBsAg-positive patients carriers vs only 1.5% of 202 deaths among HBsAg-negative patients
Beasley RP, et al. Lancet. 1981;2:1129-1132.

REVEAL Study: Serum HBV DNA Level and Risk of Cirrhosis

Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC among untreated HBsAg-positive individuals in Taiwan
14 Multivariate-Adjusted HR 12 10 8 6 4 2 0 < 300 300-9,999 10,00099,999 100,000999,999 1 million 2.0 1.0 1.0 1.9 3.6 3.4 All participants (N = 3482) HBeAg negative (n = 2960) 9.7 9.1
11.6
10. 6
HBV DNA (copies/mL)

Iloeje UH et al. Gastroenterology. 2006;130:678-686.

REVEAL Study: Serum HBV DNA Level and Risk of HCC

12 Multivariate-Adjusted HR 10 8 All participants (N = 3653) HBeAg negative (n = 3088)
10.6
6.6
6.1
6.1
6
4 2.3 2 0 < 300 300-9,999 10,00099,999 100,000999,999 1 million 1 1 1.1 1 2.6
HBV DNA (copies/mL)

Chen CJ, et al. JAMA. 2006;295:65-73.

REVEAL Study: Risk of HCC and Cirrhosis According to Baseline HBV DNA
HBV DNA, copies/mL HBV DNA, copies/mL
1.4
1.2 HCC (% per Yr)[1] 1.0 0.8 0.6 0.4
Cirrhosis (% per Yr)[2]
< 300 300-9999 10,000-99,999 100,000-999,999 1 million
3.0
2.5 2.0
< 300 300-9999 10,000-99,999 100,000-999,999 1 million
1.5
1.0 0.5 0
0.2
0
1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

Cumulative Incidence of HCC and Survival in HBeAg-Positive CHB Male Patients

100
Cumulative Incidence (%)
Survival
75
Treated group (n = 67) P = .018
50
Control group (n = 34)
25
HCC
Control group (n = 34) P = .013 Treated group (n = 67) 4 6 8 Yr of Follow-up 10 12
0 0 2
Lin SM, et al. Hepatology. 1999;29:971-975.

Recommendations for HCC Screening and Surveillance of Hepatitis B Carriers

US examination every 6-12 mos recommended for:
Asian males aged 40 yrs or older Asian females aged 50 yrs or older All cirrhotic hepatitis B carriers Persons with a family history of HCC Africans aged older than 20 yrs
Any carrier aged older than 40 yrs with persistent or intermittent ALT elevation and/or high HBV DNA level > 2000 IU/mL
Any carrier who has other risks for HCC
Bruix J, et al. AASLD HCC guidelines. July 2010. Lok AS, McMahon BJ. Hepatology. 2009;50:661-662.

Periodic Surveillance for HCC

AASLD practice guidelines for HCC recommend surveillance of hepatitis B carriers at high risk of HCC with ultrasound every 6-12 mos and AFP alone when ultrasound is not available or cost is an issue
Sensitivity, specificity, and diagnostic accuracy of ultrasound are higher than those of AFP
Since interpretation of ultrasound findings is operator dependent, clinicians may choose to use both ultrasound and AFP for HCC surveillance
Bruix J, et al. Hepatology. 2011;53:1020-1022. Lok AS, McMahon BJ. Hepatology. 2009;50:661-662.

Assessing Persons at Risk of Progression, Cirrhosis, and Cancer

Risk Factor
Smoking Alcohol Fatty liver Age Sex M > F Elevated HBV DNA and ALT Elevated ALT Fibrosis Cirrhosis
Recommended Action
Stop Discontinue Lose weight Cannot intervene No action needed First-line treatment Confirm the cause of elevation Fully evaluate and stage Do not miss this disease state
Genotype C+
Precore and core promoter mutations Coinfection with HIV/HCV/HDV
Use as part of your composite risk assessment

Use as part of your composite risk assessment Test all patients
Family history of HCC
Strongly affects treatment decisions

Summary: Monitoring a Patient Who Is CHB Positive But Not in Need of Treatment
For patients who are not candidates for immediate treatment according to guidelines
Monitor HBV and ALT levels regularly Consider HCC screening in relevant population Intervene as appropriate to manage patients health and lifestyle
HBV DNA levels are the anchor for treatment considerations

However, individual patient characteristics need to be considered when discussing treatment and interventions
Monitoring Patients Receiving CHB Treatment

PegIFN vs Nucleos(t)ide Analogues

PegIFN Pro Con Nucleos(t)ide Analogues Pro Con
Finite course of
therapy No resistance Higher rate of HBeAg loss in 1 yr Higher rate of HBsAg loss with short duration therapy*[1]
SQ administration Frequent AEs Contraindicated in

patients with cirrhosis, in pregnancy, with acute hepatitis B, and who are immunosuppressed
PO
administration Infrequent AEs ETV approved for patients with decompensated disease[2]
Need for longterm or indefinite therapy Potential for drug resistance
*Particularly for HBeAg-positive patients with genotype A infection. Risk of lactic acidosis higher in patients with advanced liver disease.[2-3]
1. Buster EH, et al. Gastroenterology. 2008;135:459-467. 2. Entecavir [package insert]. 2010. 3. Tenofovir [package insert]. 2010.

When Should PegIFN Be Considered for HBV Therapy?

Favorable predictors of response[1,2]
Low HBV DNA* High ALT*
Specific patient demographics[1,2]

Generally young people
Young women wanting pregnancy in near future
Genotype A or B > C or D[3-5]
Absence of comorbidities
Patient preference[1,2]
Concomitant HCV infection

*Also predictive of response to nucleos(t)ide analogues.
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL, et al, Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al. Am J Gastroenterol. 2006;101:297-303.

Quantitative HBsAg in Patients Receiving PegIFN

Levels of serum HBsAg crudely reflect levels of hepatic cccDNA[1] Several studies indicate serum HBsAg levels indicative of likelihood of response to pegIFN therapy[2-5]
In HBeAg-negative patients, early serum HBsAg loss found to predict SVR (undetectable HBV DNA 24 wks after treatment)
> 0.5 log10 IU/mL decrease at Wk 12 and > 1.0 log10 IU/mL decrease at Wk 24[4]
In HBeAg-positive patients, nonresponse (defined as failure to achieve HBeAg loss with HBV DNA < 10,000 copies/mL at Wk 26 posttreatment) observed in 97% of patients who failed to achieve any decline in HBsAg at Wk 12[5]
May help clinicians define stopping rules for pegIFN once commercially available in the near future
1. Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758. 2. Gish RG, et al. Am J Gastroenterol. 2007;102:2718-2723. 3. Manesis EK, et al. Antivir Ther. 2007;12:73-82. 4. Moucari R, et al. Hepatology. 2009;49:1151-1157. 5. Sonneveld MJ, et al. Hepatology. 2010;52:1251-1257.

Quantitative HBsAg and HBV DNA Predict SVR in HBeAg-Negative CHB on PegIFN
102 patients on PegIFN RBV x 48 wks
HBsAg decline at Wk 12
No (n = 54; 53%)
Yes (n = 48; 47%)
HBV DNA decline at Wk 12
< 2 logs (n = 20; 20%)
2 logs (n = 34; 33%)
< 2 logs (n = 20; 20%)
2 logs (n = 28; 27%)
Chance of sustained response (HBV DNA < 4 logs at Wk 72)
0% Stopping Rule
24%
25%
39%
Rijckborst V, et al. Hepatology. 2010;52:454-461.

IL28B May Predict Response to PegIFN in HBeAg-Positive Patients

205 HBeAg-positive patients treated with pegIFN LAM or IFN[1]
Important baseline characteristics
Race: 65% Asian; 29% white Genotypes: 13% A; 20% B; 47% C; 13% D
IL28B genotype (AA vs AG/GG) an independent predictor of HBeAg seroconversion at end of treatment
OR: 3.16 (95% CI: 1.26-8.52; P = .013)
151 white patients (85% HBeAg negative) with genotype D virus treated with pegIFN or IFN[2]
No association between IL28B genotype and HBsAg clearance (P = .28)
1. Sonneveld MJ, et al. EASL 2011. Abstract 71. 2. Mangia A, et al. EASL 2011. Abstract 1331.

Guideline Monitoring Recommendations for Interferon

Current guideline recommendations[1,2]
Liver Chemistry, CBC
During treatment Posttreatment q4w
HBV DNA, TSH

q12w
HBeAg/Anti-HBe
HBsAg
q24w*
12 and 24 wks
q6m
* If HBeAg+. If HBeAg- with serum HBV DNA persistently undetectable by PCR assay.
While further research is needed to determine the role of quantitative HBsAg in predicting response to pegIFN, in case of a primary nonresponse (ie, failure to achieve a 1 log10 reduction in HBsAg from baseline at Wk 12), pegIFN should be stopped and replaced by a nucleos(t)ide[2]
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. EASL. J Hepatol. 2009;50:227-242.

Consequences of Antiviral Resistance

Virologic breakthrough; loss of initial virologic, biochemical, and histologic response
Can lead to loss of initial response and, in some cases, hepatitis flares and hepatic decompensation, death, or urgent transplant Cross-resistance limits future treatment options Subsequent requirement for dual therapy
Transmission to treatment-naive persons poses a potential public health problem

Vaccine failure

Commercial Assays to Detect Drug-Resistant HBV

Test
Line probe assay
Advantages
~ 4% to 5% sensitivity (better than sensitivity of sequencing), detects mixed populations[1] Sequences entire RT region
Disadvantages
Limited access Not FDA approved
Integrated HBV genotype and resistance sequencing Standard sequencing
20% sensitivity[2] Not FDA approved 20% sensitivity[3] Not FDA approved
Sequences entire RT region
1. Degertekin B, et al. J Hepatol. 2009;50:42-48. 2. Woo HY, et al. Antivir Ther. 2007;12:7-13. 3. Lok AS, et al. Hepatology. 2007;46:254-265.

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

Not head-to-head trials; different patient populations and trial designs
Yr 1 Drug Generation Yr 2 Yr 3 Yr 4 Yr 5 Yr 6
1st
LAM
24%
38%
49%
67%
70%
2nd
3rd
ADV LdT ETV TDF
0% 4% 0.2% 0%
3% 17% 0.5% 0%
11% 1.2% 0%
18% 1.2% 0%
29%
1.2%
1.2%
EASL. J Hepatol. 2009;50:227-242. Tenney DJ, et al. EASL 2009. Abstract 20. Snow-Lampart A, et al. Hepatology. 2011;53:763-773. Snow-Lampart A, et al. AASLD 2010. Abstract 1365.

Correlation Between HBsAg and HBeAg Levels and Response on Entecavir

95 treatment-naive HBV patients on entecavir for 2 yrs enrolled
qHBsAg and qHBeAg levels measured at baseline and every 6 mos
Baseline qHBsAg level significantly correlated with virologic response (HBV DNA < 60 copies/mL at 24 mos) in HBeAg-positive patients
On-treatment decline in qHBeAg significantly correlated with serologic response (HBeAg loss at 24 mos) in HBeAg-positive patients
Lee JM, et al. Hepatology. 2011;53:1486-1493.

Guideline Monitoring Recommendations for Nucleos(t)ides

Liver Chemistry During treatment q12w HBV DNA q12-24w HBeAg/Anti-HBe q24w* Serum Creatinine q12w HBsAg q6-12m
*If HBeAg positive. For patients receiving adefovir or tenofovir. If HBeAg negative with serum HBV DNA persistently undetectable by PCR assay.
Breakthrough infection: > 1 log10 increase in HBV DNA above nadir after response
Assess for compliance and resistance and consider rescue therapy
Primary nonresponse: < 1 log10 decrease in HBV DNA after 12 wks of therapy (EASL)[1] or < 2 log10 decrease after 24 wks of therapy (AASLD)[2]
If detected, alternative treatments should be considered
Partial response: decrease in HBV DNA > 1 log10 IU/mL but detectable[1]
If detected, consider change of therapy
1. EASL. J Hepatol. 2009;50:227-242. 2. Lok AS, et al. Hepatology. 2009;50:661-662.

Partial Response in HBV Patients Receiving Nucleos(t)ide Therapy

Partial responders should be considered for change of therapy
Assessed at Wk 24 for lamivudine, telbivudine, and adefovir[1]
Assessed at Wk 48 for entecavir and tenofovir due to reduced likelihood of resistance development[1]
Recent study suggests partial responders to entecavir may benefit from prolonged therapy without observed resistance development[2]
1. EASL. J Hepatol. 2009;50:227-242. 2. Zoutendijk R, et al. Hepatology. 2011;[Epub ahead of print].

Important to Distinguish True Virologic Breakthrough From Nonadherence

Nearly 40% of virologic breakthroughs not related to drug resistance[1]
In patients with suspected virologic breakthrough[2]
Check for medication compliance Confirm antiviral resistance with genotypic testing
Important to determine cause of virologic breakthrough to avoid unnecessary changes in treatment regimen
1. Hongthanakorn C, et al. Hepatology. 2011;53:1854-1863. 2. Lok AS, et al. Hepatology. 2009;50:661-662.

Summary
The foundation of clinical care is accurate patient history and physical exam
In addition, for acute and chronic HBV infections, we must look to our robust armamentarium of tests to augment and decipher a patients clinical status and prognosis The use of liver enzymes, liver function tests, serologic markers, and nucleic acid tests all provide the fuel to accelerate our care vehicle to result in better patient outcomes
Go Online for Additional Resources on Virologic and Serologic Testing in HBV

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Bringing Into Focus: A Practical Guide to Using Virologic and Serologic Tests in the Management of Hepatitis B

Using Virologic and Serologic Tests in the Management of Hepatitis B

About These Slides

Using Virologic and Serologic Tests in the Management of Hepatitis B

Using Virologic and Serologic Tests in the Management of Hepatitis B

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence 8% (high) 2% to 7% (intermediate) < 2% (low)

Using Virologic and Serologic Tests in the Management of Hepatitis B

The HBV Iceberg

2 million individuals in the US have chronic HBV infection

300,000 are diagnosed in care

Population-based studies allow us to look at the whole iceberg

1.4 million are unaware of their chronic HBV infection

Cohen C, et al. J Viral Hepatitis. 2011;18:377-383. Graphic reproduced with permission.

Using Virologic and Serologic Tests in the Management of Hepatitis B

Groups at High Risk for HBV Infection Who Should Be Screened

Men who have sex with men

Lok AS, et al. Hepatology. 2009;50:661-662.

Initial Evaluation and Tests to Diagnose HBV

Using Virologic and Serologic Tests in the Management of Hepatitis B

Assessing Patient History and Current Presentation

Patient motivation, compliance, adherence

Using Virologic and Serologic Tests in the Management of Hepatitis B

Hepatitis B Serology: First Phase Testing

Using Virologic and Serologic Tests in the Management of Hepatitis B

Why Do We Need to Do Anti-HBc Testing?

Chemoprophylaxis for HBV reactivation

Assess risk of donor HBV transmission

Using Virologic and Serologic Tests in the Management of Hepatitis B

Hepatitis B Serology: IgM anti-HBc

Presence indicates acute infection (negative in chronic infection)

Occasionally occurs in the presence of a severe flare of chronic HBV disease

Using Virologic and Serologic Tests in the Management of Hepatitis B

Interpretation of Serologic Results

CDC. Hepatitis B FAQs for health professionals. Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm.

Using Virologic and Serologic Tests in the Management of Hepatitis B

Initial Testing in Patients Diagnosed With Chronic HBV

Using Virologic and Serologic Tests in the Management of Hepatitis B

Hepatitis B Serology: Determining HBeAg Status in CHB Patients

Using Virologic and Serologic Tests in the Management of Hepatitis B

Precore and core promoter mutations[3]

Genotypes Treatment-induced mutations

Using Virologic and Serologic Tests in the Management of Hepatitis B

Natural History of HBV Infection

Using Virologic and Serologic Tests in the Management of Hepatitis B

Using Virologic and Serologic Tests in the Management of Hepatitis B

HBV Classified Into 10 Genotypes

Using Virologic and Serologic Tests in the Management of Hepatitis B

Why Test for HBV Genotype?

C has higher risk of HCC and cirrhosis

Using Virologic and Serologic Tests in the Management of Hepatitis B

Summary: Tests for Initial Evaluation and Diagnosis of HBV

Tests to Determine Treatment Candidacy

Using Virologic and Serologic Tests in the Management of Hepatitis B

Parameters Used to Determine Candidates for Treatment of HBV

Using Virologic and Serologic Tests in the Management of Hepatitis B

Transmission of HBV Is Proportional to HBV DNA Level

Mother > 106-8 IU/mL Perinatal

Using Virologic and Serologic Tests in the Management of Hepatitis B

Natural History of HBV: Directly Related to HBV DNA Level

10% to 15% in 5 yrs Cirrhosis 23% in 5 yrs Liver transplantation* Death

Using Virologic and Serologic Tests in the Management of Hepatitis B

Treatment Criteria for Chronic Hepatitis B: Comparison of Guidelines