Management of the Management of the Immune Tolerant Phase of Immune Tolerant Phase of

Chronic Hepatitis BChronic Hepatitis BMaiyen Tran Hawkins, PGY-3Maiyen Tran Hawkins, PGY-3

Georgetown University HospitalGeorgetown University HospitalDepartment of Internal MedicineDepartment of Internal Medicine

Advisor: James H. Lewis, MDAdvisor: James H. Lewis, MDOctober 28, 2009October 28, 2009

Chronic Hepatitis B:Chronic Hepatitis B:Three PhasesThree Phases

Immune Active PhaseImmune Active Phase Elevated HBV DNAElevated HBV DNA Elevated ALT levelsElevated ALT levels Active liver inflammationActive liver inflammation

Inactive PhaseInactive Phase HBV DNA <2,000 IU/mLHBV DNA <2,000 IU/mL Normal ALT levelsNormal ALT levels Liver Histology revealing at least minimal Liver Histology revealing at least minimal

inflammation and fibrosisinflammation and fibrosis

Immune Tolerant PhaseImmune Tolerant Phase HBV DNA >20,000 IU/mL (10HBV DNA >20,000 IU/mL (1055 copies/mL) copies/mL) Normal ALT levelsNormal ALT levels No significant inflammation/fibrosis on liver No significant inflammation/fibrosis on liver

histologyhistology HBeAg PositiveHBeAg Positive

Chronic Hepatitis B:Chronic Hepatitis B:Three PhasesThree Phases

Immune Tolerant PhaseImmune Tolerant Phase

Commonly perinatally acquiredCommonly perinatally acquired Frequently in Foreign-born individuals Frequently in Foreign-born individuals

Those who should be screenedThose who should be screened

Immune Tolerant PhaseImmune Tolerant Phase

Commonly perinatally transmittedCommonly perinatally transmitted Frequently in Foreign-born individualsFrequently in Foreign-born individuals A patient may traverse through phasesA patient may traverse through phases 10-30 years10-30 years Persistently elevated HBV DNA levels contribute Persistently elevated HBV DNA levels contribute

to increased risk of HCC to increased risk of HCC

Immune Tolerant PhaseImmune Tolerant Phase

HBV is not directly cytotoxicHBV is not directly cytotoxic Immune response mediates hepatocyte injury Immune response mediates hepatocyte injury ““HBeAg – Expressing transgenic mice in vivo HBeAg – Expressing transgenic mice in vivo

have reduced anti-HBe Ab production reflects have reduced anti-HBe Ab production reflects diminished Th-cell fxn. Expression of HBeAg diminished Th-cell fxn. Expression of HBeAg may represent a viral strategy to guarantee may represent a viral strategy to guarantee persistence after perinatal infection.”persistence after perinatal infection.”

Milich, DR et al. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Immunology. Sept Milich, DR et al. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Immunology. Sept 1990. vol. 87, pp6599-6603. (Scripps)1990. vol. 87, pp6599-6603. (Scripps)

Current AASLD Practice Current AASLD Practice Guidelines 2009Guidelines 2009

Low efficacy with current treatmentLow efficacy with current treatment Observe, consider treatment if ALT becomes Observe, consider treatment if ALT becomes

elevatedelevated Consider biopsy: aged >40, ALT persistently Consider biopsy: aged >40, ALT persistently

elevated, family hx HCCelevated, family hx HCC Consider treatment: HBV DNA >20,000 IU/mL Consider treatment: HBV DNA >20,000 IU/mL

AND biopsy shows mod/sev inflammation and AND biopsy shows mod/sev inflammation and significant fibrosissignificant fibrosis

Goals of TherapyGoals of Therapy

Maintain suppression of HBV DNA Maintain suppression of HBV DNA replicationreplication

Prevent cirrhosisPrevent cirrhosis Prevent hepatic failurePrevent hepatic failure Prevent HCCPrevent HCC

To Treat or Not To TreatTo Treat or Not To Treat The Risk Evaluation of the Viral Load Elevation and The Risk Evaluation of the Viral Load Elevation and

Associated Liver Disease/Cancer (REVEAL) HBV studyAssociated Liver Disease/Cancer (REVEAL) HBV study The results “The results “demonstrate that serum HBV DNA demonstrate that serum HBV DNA

level is likely the most important modifiable level is likely the most important modifiable risk predictor of developing HCC risk predictor of developing HCC .”.”

CJ Chen, HI Yang, J Su, and others. Serial monitoring of viral load and serum alanine CJ Chen, HI Yang, J Su, and others. Serial monitoring of viral load and serum alanine aminotranferase level and the risk of hepatocellular carcinoma (HCC): R.E.V.E.A.L.-HBV aminotranferase level and the risk of hepatocellular carcinoma (HCC): R.E.V.E.A.L.-HBV study update. 43rd annual meeting of the European Association for the Study of the Liver study update. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.(EASL 2008). Milan, Italy. April 23-27, 2008.

““Sustained clearance of HBeAg was achieved only in 8 Sustained clearance of HBeAg was achieved only in 8 (15%) of treated patients at 12 months. Between 12 and (15%) of treated patients at 12 months. Between 12 and 24 months 3 (9%) of treated patients and 1 control 24 months 3 (9%) of treated patients and 1 control became negative for HBeAg.” became negative for HBeAg.” Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up on a randomised trial of Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up on a randomised trial of

recombinant alpha-2-interferon in Chinese patients with Chronic Hepatitis B. Lancet recombinant alpha-2-interferon in Chinese patients with Chronic Hepatitis B. Lancet 1988;2(8606):298-302. 1988;2(8606):298-302.

““An HBV DNA level <2,000 copies/mL at 6 months after lamivudine An HBV DNA level <2,000 copies/mL at 6 months after lamivudine therapy is the most important predictor of HBeAg loss during up to 1 therapy is the most important predictor of HBeAg loss during up to 1

year of lamivudine therapy.”year of lamivudine therapy.” Jun JK et al, Change of HBV DNA level as a predictor of HBeAg loss after lamivudine treatment. Korean Jun JK et al, Change of HBV DNA level as a predictor of HBeAg loss after lamivudine treatment. Korean

Journal of Hepatology. 2007 Dec; 13(4): 513-520.Journal of Hepatology. 2007 Dec; 13(4): 513-520.

To Treat or Not To TreatTo Treat or Not To Treat

To Treat or Not To TreatTo Treat or Not To Treat

Cost-effectiveness of Suppressing Hepatitis Cost-effectiveness of Suppressing Hepatitis B Virus DNA in Immune Tolerant Patients to B Virus DNA in Immune Tolerant Patients to Prevent Hepatocellular Carcinoma and Prevent Hepatocellular Carcinoma and CirrhosisCirrhosis Enriquez, AD Campbell, MS, Reddy, KR. Alimentary Enriquez, AD Campbell, MS, Reddy, KR. Alimentary

Pharmacology and Therapeutics 8/2007.Pharmacology and Therapeutics 8/2007. Markov Model: HBV DNA suppression w/ lamivudine and no Markov Model: HBV DNA suppression w/ lamivudine and no

treatmenttreatment Lamivudine more expensive, but more cost effective Lamivudine more expensive, but more cost effective TreatmentTreatment gain in life expectancy and decrease in lifetime gain in life expectancy and decrease in lifetime

risk of HCC and cirrhosisrisk of HCC and cirrhosis

QuestionnaireQuestionnaire

Do you treat? If not, when you would?Do you treat? If not, when you would? Studies to follow?Studies to follow? Liver biopsy?Liver biopsy? First line of therapy?First line of therapy? Goals/Endpoints of Therapy?Goals/Endpoints of Therapy? Duration of therapy?Duration of therapy?

DemographicsDemographics

Physician ProfilePhysician Profile Over 20 years in Over 20 years in

practicepractice Mainly Hepatology, Mainly Hepatology,

some general some general GastroenterologyGastroenterology

Directors of Directors of Hepatology—VA, MD, Hepatology—VA, MD, DC, NY, ChicagoDC, NY, Chicago Dallas, California, Dallas, California,

BostonBoston

Patient PopulationPatient Population 2/3 Male2/3 Male 95%-100% Asian95%-100% Asian Age bracket 20-30Age bracket 20-30

ResultsResults

All do not treat unless there is strong All do not treat unless there is strong Family h/o HCC, on Family h/o HCC, on chemotherapy/cytotoxic meds, or are chemotherapy/cytotoxic meds, or are pregnant—2pregnant—2ndnd-3-3rdrd trimester. trimester.

Reasons: Natural hx is not well Reasons: Natural hx is not well understood; committing to decades of understood; committing to decades of therapy; Guidelines are based on therapy; Guidelines are based on evidenceevidence

StudiesStudies

ALT, HBeAG, HBV DNA q6 monthsALT, HBeAG, HBV DNA q6 months HCC Screening with U/S and AFP level q HCC Screening with U/S and AFP level q

6 months if positive family history.6 months if positive family history.

Liver BiopsyLiver Biopsy

1/6 respondents said yes to ALL ITHB pts.1/6 respondents said yes to ALL ITHB pts. Age >40Age >40 ALT upper limits of nmlALT upper limits of nml FibroSpect also used: biomarkers which FibroSpect also used: biomarkers which

includeinclude Alpha 2-macroglobulin, haptoglobin, GGT, Alpha 2-macroglobulin, haptoglobin, GGT,

ALT, PT, PLTs, apolipoprotein A1, hyaluronic ALT, PT, PLTs, apolipoprotein A1, hyaluronic acid, TIMP-1 (acid, TIMP-1 (tissue inhibitor of tissue inhibitor of metalloproteinasesmetalloproteinases) )

Start treating…Start treating…

When HBV DNA >1 millionWhen HBV DNA >1 million ALT upper limits of normalALT upper limits of normal Mod to severe inflammation/fibrosisMod to severe inflammation/fibrosis 22ndnd – 3 – 3rdrd Trimester pregnancy Trimester pregnancy Immunosuppressive therapyImmunosuppressive therapy

First line of therapyFirst line of therapy

EntecavirEntecavir Tenofovir (less expensive)Tenofovir (less expensive)

May change to Truvada (Tenofovir and May change to Truvada (Tenofovir and Emtricitibine)Emtricitibine)

Goals of TherapyGoals of Therapy

Seroconversion HBeAg Seroconversion HBeAg (occurrence 10-15%)(occurrence 10-15%)

Ultimately, prevention of HCCUltimately, prevention of HCC

ReferencesReferences CJ Chen, HI Yang, J Su, and others. Serial monitoring of viral load and serum alanine CJ Chen, HI Yang, J Su, and others. Serial monitoring of viral load and serum alanine

aminotranferase level and the risk of hepatocellular carcinoma (HCC): R.E.V.E.A.L.-HBV study aminotranferase level and the risk of hepatocellular carcinoma (HCC): R.E.V.E.A.L.-HBV study update. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). update. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.Milan, Italy. April 23-27, 2008.

Enriquez, AD Campbell, MS, Reddy, KR, Cost-effectiveness of Suppressing Hepatitis B Virus Enriquez, AD Campbell, MS, Reddy, KR, Cost-effectiveness of Suppressing Hepatitis B Virus DNA in Immune Tolerant Patients to Prevent Hepatocellular Carcinoma and Cirrhosis. Alimentary DNA in Immune Tolerant Patients to Prevent Hepatocellular Carcinoma and Cirrhosis. Alimentary Pharmacology and Therapeutics. 8/2007;26(3):383-391. Pharmacology and Therapeutics. 8/2007;26(3):383-391.

Jun JK et al, Change of HBV DNA level as a predictor of HBeAg loss after lamivudine treatment. Jun JK et al, Change of HBV DNA level as a predictor of HBeAg loss after lamivudine treatment. Korean Journal of Hepatology. 2007 Dec; 13(4): 513-520.Korean Journal of Hepatology. 2007 Dec; 13(4): 513-520.

Lok, A. and McMahon, B. Chronic Hepatitis B: Update 2009; AASLD Practice Guidelines. Lok, A. and McMahon, B. Chronic Hepatitis B: Update 2009; AASLD Practice Guidelines. Published online in Wiley InterScience (www.interscience. wiley.com).Published online in Wiley InterScience (www.interscience. wiley.com).

Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up on a randomised trial of recombinant Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up on a randomised trial of recombinant alpha-2-interferon in Chinese patients with Chronic Hepatitis B. Lancet 1988;2(8606):298-302. alpha-2-interferon in Chinese patients with Chronic Hepatitis B. Lancet 1988;2(8606):298-302.

McMahon, B. The Natural History of Chronic Hepatitis B Virus Infection. Hepatology 2009; McMahon, B. The Natural History of Chronic Hepatitis B Virus Infection. Hepatology 2009; 49:S45-S55.49:S45-S55.

Milich, DR et al. Is a function of the secreted hepatitis B eantigen to induce Milich, DR et al. Is a function of the secreted hepatitis B eantigen to induce immunologic tolerance in utero? Immunology. Sept 1990. vol. 87, pp6599-6603. immunologic tolerance in utero? Immunology. Sept 1990. vol. 87, pp6599-6603. (Scripps)(Scripps)

NIH consensus development statement on management of hepatitis B. 2008, Oct NIH consensus development statement on management of hepatitis B. 2008, Oct 22-24;25(2):1-29.22-24;25(2):1-29.

Thank you!Thank you!

QUESTIONS?QUESTIONS?