1. Ask the Experts: Hepatitis B & C Treatment and Liver Cancer Screening
F. Blaine Hollinger, M.D.
Kathleen B. Schwarz, M.D.
Leonard B. Seeff, M.D.
Coleman I. Smith, M.D.
Deborah L. Wexler, M.D. - Moderator

2. Hepatitis B Treatment Questions (1)
How do you define a person who is chronically infected with HBV, i.e., how do you select patients to follow for chronic HBV infection? (lab test definition)
What blood tests and other studies do you recommend for those who are chronically infected with HBV and with what frequency should they be done? How often should they see a health professional for these tests? What kind of health professional should they see? (adults and children)
What tests should be done to screen an HBsAg-positive patient for liver cancer and how often should these tests be done? ( adults and children)
What are the criteria you look for to determine which patients need treatment for chronic hepatitis B? (adults and children)
What medications are available for the treatment of hepatitis B and how are they administered (SQ, IM) and for what period of time? How do you determine which medication(s) to use?

3. Hepatitis B Treatment Questions (2)
What are the side effects of these medications? How effective are these treatments? (adults and children)
How do you determine who needs a liver biopsy and please describe how a liver biopsy is done (patient asleep?, how long, how many samples?) (adults and children)
Why can’t these medications be used on everyone who is HBsAg positive?
Are there any treatment regimens in clinical trials that look like they will be more effective treatments? (adults and children)
What treatment options are available for people without health insurance?
How does a patient choose a specialist in liver disease?
What should be done for family members and sex partners of patients who are HBsAg positive?

4. Hepatitis C Treatment Questions (1)
How do you diagnose a person who is chronically infected with HCV? (How do you differentiate between a person who is chronically infected with HCV and a person with chronic HCV disease.)
What blood tests and other studies do you recommend for those who are identified as HCV positive and with what frequency should the tests be done? How often should they see a health professional for these tests? What kind of health professional should they see? (adults and children)
How do you determine who needs a liver biopsy?
What tests should be done to screen an HCV-positive patient for liver cancer and how often should these tests be done? (adults and children)
What are the criteria you look for to determine which patients need treatment for chronic hepatitis C? (adults and children)

5. Hepatitis C Treatment Questions (2)
What medications are available for the treatment of hepatitis C and how are they administered (SQ, IM) and for what period of time? How do you determine which treatment to use? What are the side effects of these medications? How effective are these treatments? (adults and children)
Why aren’t these medications used on everyone who is HCV positive?
Are there any treatment regimens in clinical trials that look like they will be more effective treatments? (adults and children)
What education should be given to family members and sex partners of patients who are HCV positive?
What treatment options are available for people without health insurance?

6. Hepatitis B Glossary
HBsAg: Hepatitis B surface antigen. Marker of infectivity when found in serum.
anti-HBs: Antibody to HBsAg. Marker of immunity when found in serum.
HBcAg: Hepatitis B core antigen. No commercial test available for this.
anti-HBc: Antibody HBcAg. Marker of past or current infection.
IgM anti-HBc: IgM is an antibody subclass of anti-HBc. Indicates recent infection with HBV (<4-6 mos.).
IgG anti-HBc: IgG is a subclass of anti-HBc. Indicates “older” infection with HBV.
HBeAg: Hepatitis B “e” antigen. Can only be present if HBsAg is positive. Marker of high degree of infectivity.
Anti-HBe: Antibody to “e” antigen. May be present in infected or immune person.

7. Acute HBV Infection with Recovery
Typical Serologic Course
HBeAg
anti-HBe
Symptoms
Total anti-HBc
Titer
anti-HBs
HBsAg
IgM anti-HBc 4 8 12 16 20 24 28 32 36 52
100
Weeks after Exposure 30

8. Progression to Chronic HBV Infection
Typical Serologic Course
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
IgM anti-HBc 4 8 12 16 20 24 28 32 36 52
Years
Weeks after Exposure 31

9. Interpretation of Hepatitis B Panel
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 positive acutely infected
IgM antiHBc positive
antiHBs negative
HBsAg positive
antiHBc positive chronically
IgM antiHBc negative infected
antiHBs negative
HBsAg negative
antiHBc positive four possible interpretations
antiHBs negative (see next slide)

10. Four possible interpretations of isolated antiHBc positive
1. May be recovering from acute HBV infection.
2. May be distantly immune and test not sensitive enough to detect very low level of anti-HBs in serum.
3. May be susceptible with a false positive anti-HBc.
4. May be undetectable level of HBsAg present in the serum and the person is actually a carrier.

11. Liver Biopsy and How It’s Done(1)
Indications: assessment of diagnosis and severity pre-treatment
Contraindications: coagulopathy, ascites, non-palpable liver
Complications: bleeding 1/1000, perforation of lung, intestine, or gallbladder (rare); pain; infection; inadvertent biopsy of kidney or spleen; complication of sedation

12. Liver Biopsy and How It’s Done (2)
Ultrasound guidance or site selection
Sedation with iv midazolam/fentanyl
Sterile preparation/lidocaine s.q.
3mm incision/needle biopsy
Submission for light microscopy and special stains, EM, culture
Monitoring, hemoglobin, vital signs

13. Liver Biopsy: a picture’s worth a thousand words

14. Treatment for Chronic HBV
Three FDA-licensed treatment options available for adults in the United States
interferon alfa-2b (IntronA), recombinant administered subcutaneously qd or 3x/wk
also licensed for use in children
lamivudine (Epivir-HB) administered by mouth qd
adefovir dipivoxil (Hepsera) administered by mouth qd
Consult a liver specialist to assist in determining whether your patient is a treatment candidate.

15. Tumor Markers of Hepatocellular Carcinoma
Advantages
Disadvantages
Alpha-fetoprotein
Relatively quick and easy; extensively studied
Relatively expensive
Des-gamma-carboxyprothrombin
Quick and easy
Much more expensive
Alpha-L-fucosidase
Quick and easy; relatively inexpensive

16. Tumor Markers of Hepatocellular Carcinoma
Sensitivity
Specificity
Alpha-fetoprotein
80-90%
(high incidence area)
50-70%
(low incidence area)
90%
Des-gamma-carboxyprothrombin
58-91%
84%
Alpha-L-fucosidase
75%
70-90%

17. Hepatitis C Glossary HCV: Hepatitis C virus
Anti-HCV: Antibody to hepatitis C virus
EIA: Enzyme immunoassay
ELISA: Enzyme-linked immunoassay
RIBA: Recombinant immunoblot assay
HCV RNA: HCV ribonucleic acid
PCR: Polymerase chain reaction
RT-PCR: Reverse transcription polymerase chain reaction
TMA: Transcription-mediated amplification
ETR: End of treatment response
SVR: Sustained virological response

18. Assays for Hepatitis C
Anti-HCV: EIAs have excellent sensitivity and specificity
 False pos. <1% in low risk populations, blood donors
 False neg. <1% in immune deficiencies, HIV, renal dis.
HCV RNA: PCRs have high sensitivity ( copies/ml)
and are FDA licensed
HCV RNA level: several available assays, none FDA
approved, competitive PCR with sensitivity of 500 copies,
linear range ,000 copies/ml
Genotype assays: none FDA approved but several available
(LIPA, sequencing) most reliable

19. EIA Assays for Hepatitis C
Assay Epitopes
Ortho HCV 3.0 ELISA Test Core, NS3, NS4, NS5
System with enhanced SAVe
Vitros anti-HCV (Ortho) Core, NS3, NS4, NS5
Abbott HCV EIA Core, NS3, NS4, NS5
Abbott HCV EIA Core, NS3, NS4, NS5

20. Qualitative Assays for HCV RNA
Assay Manufacturer HCV RNA
Cutoff (IU)
PCR-based:
Amplicor HCV v Roche Molecular Systems IU/mL
Cobas Amplicor Roche Molecular Systems IU/mL
HCV v2.0
TMA-based:
Versant HCV RNA Bayer Corporation IU/mL
Qualitative Assay

21. Quantitative Assays for HCV RNA
Assay Manufacturer Dynamic Range
Amplicor HCV Roche Mol. Systems <500,000 IU/mL
Monitor v2.0
Cobas Amplicor Roche Mol. Systems <500,000 IU/mL
HCV Monitor v2.0
Versant HCV RNA Bayer Corporation , ,000,000
2.0 Quant. Assay genome equivs/mL
Versant HCV RNA Bayer Corporation ,700,000 IU/mL
3.0 Quant, Assay
LCx HCV RNA Abbott Diagnostics ,630,000 IU/mL
Quantitative Assay
SuperQuant National Genet. Inst ,470,000 IU/mL

22. Treatment of Hepatitis C Genotype 1
Pegylated interferon alfa-2b (PegIntron) 1.5 mcg/kg bw subq
once weekly, or pegylated interferon alfa-2a (Pegasys) 180 mcg
subq once per week, plus ribavirin mg (depending
on body weight) po daily in divided doses for 24 weeks. If
HCV RNA is negative at this time, continue treatment for an
additional 24 weeks. If still positive, discontinue treatment.
Note: An option is to test for HCV RNA after 12 weeks of
treatment and if HCV RNA is not negative or has not decreased
by 2 logs from the baseline, treatment can be discontinued at
this time (12 weeks).

23. Treatment of Hepatitis C Genotype 2 or 3
Pegylated interferon alfa-2b (PegIntron) 1.5 mcg/kg bw subq once weekly, or pegylated interferon alfa-2a (Pegasys) 180 mcg subq once per week, plus ribavirin 800 mg po daily in divided doses for 24 weeks.

24. Treatment of Hepatitis C Potential Outcomes of Treatment
Probable Cure: HCV RNA negative at end of treatment (end of treatment response; ETR), the negativity sustained for at least 6 months after stopping treatment (sustained virological response; SVR)
Relapse: Treatment leads to an ETR but not an SVR, i.e., HCV RNA re-detected after stopping treatment.
Partial On-Treatment Response: Decrease in HCV RNA titer while on treatment but not to an undetectable level.
 Non-Response: No impact whatsoever on viral titer

25. Clinical Trial Information
Hepatitis B Foundation:
Centerwatch:
National Institutes of Health: or call Liz Formentini at or ext 49905

26. Reimbursement Programs for Financially Needy Persons with Hepatitis B and C
Manufacturer
Generic Name
Commerical Name
1-800 Telephone
1-800 Fax
Gilead Sciences, Inc.
Adefovir dipivoxil
Hepsera
GlaxoSmithKline
Lamivudine
Epivir
InterMune Inc.
Consensus Interferon
Infergen
Roche Pharmaceuticals
Interferon alfa-2a, recombinant
Peginterferon alfa-2a
Ribavirin
Roferon-A
Pegasys
Copegus
Schering Corporation
Interferon alfa-2b, recombinant
Combination therapy (interferon alfa-2b and ribavirin)
Peginterferon alfa-2b
Intron A
Rebetron
Peg-Intron
Rebetol