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

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?

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?

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)

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?

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.

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

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

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)

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.

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

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

Liver Biopsy: a picture’s worth a thousand words

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.

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

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%

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

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 (50-100 copies/ml) and are FDA licensed HCV RNA level: several available assays, none FDA approved, competitive PCR with sensitivity of 500 copies, linear range 500-500,000 copies/ml Genotype assays: none FDA approved but several available (LIPA, sequencing) most reliable

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 2.0 Core, NS3, NS4, NS5 Abbott HCV EIA 3.0 Core, NS3, NS4, NS5

Qualitative Assays for HCV RNA Assay Manufacturer HCV RNA Cutoff (IU) PCR-based: Amplicor HCV v2.0 Roche Molecular Systems 50IU/mL Cobas Amplicor Roche Molecular Systems 50IU/mL HCV v2.0 TMA-based: Versant HCV RNA Bayer Corporation 10IU/mL Qualitative Assay

Quantitative Assays for HCV RNA Assay Manufacturer Dynamic Range Amplicor HCV Roche Mol. Systems 600-<500,000 IU/mL Monitor v2.0 Cobas Amplicor Roche Mol. Systems 600-<500,000 IU/mL HCV Monitor v2.0 Versant HCV RNA Bayer Corporation 200,000-120,000,000 2.0 Quant. Assay genome equivs/mL Versant HCV RNA Bayer Corporation 615-7,700,000 IU/mL 3.0 Quant, Assay LCx HCV RNA Abbott Diagnostics 25-2,630,000 IU/mL Quantitative Assay SuperQuant National Genet. Inst. 30-1,470,000 IU/mL

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 1000-1200 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).

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.

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

Clinical Trial Information Hepatitis B Foundation: www.hepb.org/clinicalinfo.html Centerwatch: www.centerwatch.com/studies/cat79.htm National Institutes of Health: www.clinicaltrials.gov or call Liz Formentini at 301-594-9905 or 800-772-5464 ext 49905

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 226-2056 216-6857 GlaxoSmithKline Lamivudine Epivir 722-9294 750-9832 InterMune Inc. Consensus Interferon Infergen 577-9112 Roche Pharmaceuticals Interferon alfa-2a, recombinant Peginterferon alfa-2a Ribavirin Roferon-A Pegasys Copegus 443-6676 387-1258 777-7562 Schering Corporation Interferon alfa-2b, recombinant Combination therapy (interferon alfa-2b and ribavirin) Peginterferon alfa-2b Intron A Rebetron Peg-Intron Rebetol 521-7157 683-7855