HBVCurbside consultation and case discussion in special

populations

Brenda Appolo PAC, MHSUniversity of Pennsylvania, Perelman School of Medicine

HBV: Special Populations

• Pregnancy• HBV and Risk of Reactivation• HBV and HIV co-infection• Decompensated cirrhosis• Hepatitis D• HBV and HCV co-infection• Resistant HBV• HBV in Liver Transplant Recipients

.

Clinical Profiles of Chronic HBV Infection

Immune Tolerant

HBeAg (+) CHBInactive HBsAg

Carrier

HBeAg (-) CHB (Precore

Mutant)

HBsAg + + + + HBeAg + + – – Anti-HBe – – + + ALT Normal Normal

HBV DNA>20,000 IU/mL

(>105 copies/mL)>20,000 IU/mL

(>105 copies/mL)<200 IU/mL

(<103 copies/mL)

>2,000 IU/mL

(>104* copies/mL)

Histology Normal/Mild Active Normal Active

Adapted from Hoofnagle JH et al. Hepatology. 2007;45:1056-1075.

HBeAg, hepatitis B e antigen.*Expert opinions vary as to this value

TIME

Loss of HBeAg

Loss of HBV DNA

Anti-HBe+

Loss ofHBsAg

Anti-HBs+ Improvedsurvival

Improvedhistology

Therapeutic Endpoints

= HBeAg seroconversion

Approved Therapies for Chronic HBV

First-Line Therapy

Peginterferon alfa-2a PEGASYS® Roche Laboratories 2005

Tenofovir VIREAD® Gilead Sciences 2008

Entecavir BARACLUDE™ Bristol-Myers Squibb 2005

Second-Line Therapy

Adefovir dipivoxil HEPSERA™ Gilead Sciences 2002

Telbivudine TYZEKA™ Idenix andNovartis 2006

Third-Line Therapy

Lamivudine EPIVIR-HBV® GlaxoSmithKline 1998

\.

Case #1• 33 F presents for initial HBV consultation• Moved from Belgium with husband 8 yrs ago to

US; she was born in China• 21 wks pregnant with first child; no complications• Meds: Prenatals; never treated for HBV in past• Exam: unremarkable for stigmata of liver disease• Labs

• CBC wnl• ALT 19; AST 16; T bil 0.9; AlkPhos 189; Albumin• INR 1.0• HBV s Ag +; HBV e Ag +; HBV e Ab neg• HBV > 170,000,000 iu/ml

Case #1• What other history is pertinent

• FHx: Mother HBV +; Sister HBV ?; Father HBV ?; Maternal Uncle HBV + / HCC

• Husband HBV per patient “negative”

• What other labs / imaging at this point?• What is risk of vertical transmission to baby?• Should we treat mom?

• Why? Why not?

• What should we advise mom and OB/neonatology colleagues if anything?

• HBV Vaccination & HBIg IM w/in 12 hours of birth– HBV vaccination: Birthday, 2m, 6m – Confirm Ab at one year of age

HBV and Pregnancy

Treatment of CHB in Women Considering Pregnancy

Options:• Treat prior to pregnancy - finite treatment course • Defer treatment until post-partum

– Main consideration is risk to mother in absence of treatment

– May be deferring for years if planning >1 pregnancy• Defer treatment until after first trimester

– 1st trimester is period of greatest risk for developing fetus

– Reduction of viral load may reduce risk of transmission to infant

1 Tse et al. J Hepatology 20052 Su et al. World J Gastroenterol 2004

Risk-Benefit AssessmentTreatment During Pregnancy

Possible Benefits • Prevent disease

progression during pregnancy

• Prevent flares in association with abrupt withdrawal of therapy

• Reduce risk of pre-term labor 1, 2

• Prevent intrauterine transmission

Possible Risks

• Adverse outcome of pregnancy

Antiviral Medications and Pregnancy Risk

Drugs FDA Category

Lamivudine C

Telbivudine B

Tenofovir B

Entecavir C

Adefovir C

Interferon-alfa and pegylated interferon-alfa

C

Pregnancy Categories – Drug SafetyCategory Definition

A Controlled studies show no risk: adequate, well-controlled studies in pregnant women failed to demonstrate risk to the fetus

B No evidence of risk in humans: either animal findings show risk, but human findings do not; or, if no adequate human studies have been done, animal findings are negative

C Risk cannot be ruled out: human studies are lacking, and animal studies are either positive for foetal risk, or lacking as well. However, potential benefits may justify the potential risk

D Positive evidence of risk: investigational or post-marketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the potential risk

X Contraindicated in pregnancy: studies in animals or humans, or investigational or post-marketing reports, have shown fetal risk which clearly outweighs any possible benefit to the patient.

Antiretroviral Pregnancy Registry Data

Agents

Earliest Trimester of Exposure

1st trimester birth defects / live births

2nd- 3rd trimester birth defects / live births

Lamivudine 127/4088 (3.1%) 186/6635 (2.8%)

Adefovir 0/48 0/0

Telbivudine 0/9 0/9

Tenofovir 31/1370 (2.3%) 18/782 (2.3%)

Entecavir 1/42 0/2

http://www.apregistry.com – 1 January 1989 through 31 January 2012

Estimated Risk of Perinatal HBV Transmission (without prevention)

0

20

40

60

80

100

HBeAgnegative

HBeAgpositive

0

20

40

60

80

100

Infectedduring 1sttrimester

Infectedduring 3rdtrimester

Ris

k o

f Tr

ansm

issi

on

to

In

fan

ts (

%)

Chronic HBV infected mothers

Acute hepatitis HBV infected mothers

10-40%

90%

10%

80-90%

Lamivudine in Late Pregnancy to Prevent Perinatal Transmission

0

10

20

30

40

50

LAM Placebo

0

10

20

30

40

50

LAM Placebo

• Double-blind, RCT in China

• N = 141

• HBsAg+ pregnant women

• HBV-DNA >109 copies/ml

• LAM 100 mg/D vs placebo; from GA 32 wk to 4 wk after delivery • All received HBIG + HBV vaccine

• High drop-out rate

(LAM 13%, placebo 31%)

% In

fan

t w

ith

HB

V-D

NA

po

siti

ve a

t ag

e 1

yr

ITT analysis

Based on those tested

7%15%

20%

46%

Xu WM et al. J Viral Hepat 2009;16:94-103

P=NS

P=0.003

Efficacy of Telbivudine in Late Pregnancy for Prevention of Vertical HBV Transmission

% In

fan

t w

ith

HB

sAg

+ a

t ag

e 7

mo

nth

s

0%8%

Han GR, et al. J Hepatol 2011;55:1215-21

P=0.002

• Open-labeled prospective study

• N = 141 (all Chinese)

• HBsAg+ pregnant women

• HBeAg+

• HBV-DNA >109 copies/ml

• LdT 600 mg/D vs untreated

control

• from GA 20-32 wk to delivery

• All received HBIG+HBV vaccine

0

10

20

30

40

50

LdT Placebo

Pan CQ, Mi LJ, Bunchorntavakul C, et al. Dig Dis Sci 2012;57:2423-9

Tenofovir for Prevention of HBV Vertical Transmission• Retrospective analysis• 11 HBV infected mothers with HBeAg positive; median HBV-DNA 9

(7.7-9.4) log10 copies/ml• TDF was started at the median GA of 29 (28-32) wk• Maternal outcomes

– HBV-DNA significantly reduced at delivery compared to BL – 6/11 pt. had HBV-DNA < 6 log10 before delivery– No significant changes in serum creatinine– TDF was stopped soon after delivery in 8 pt; no ALT flare

• Infant outcomes– All infants were HBsAg negative at 28-36 wk of age– No congenital defect – All infants received HBIG+HBV vaccine

Proposed Algorithm for HBV Management During Pregnancy

Buchanan C, Tran TT. Clin Liver Dis 2010;14:495-504

Case #1 – wrap up

• Should we treat mom?• How long should therapy continue?

• Is she breastfeeding

• HCC surveillance?

Case #2• 56 yr old F present to ED with new onset jaundice, malaise • PMHx – CD20-positive diffuse large B-cell non-Hodgkin's

lymphoma; completed treatment 6 weeks prior (rituximab + CHOP)

• SHx – no alcohol, previous IVDU 20 yrs ago• Meds: levothyroxine• Exam: Scleral icterus; exam otherwise unremarkable• Pretreatment labs

– Per patient LFTs normal

• ED Labs– ALT 333; AST 235; T bil 5.4; AlkPhos 241; Albumin 3.0

Case #2• What is your DDx?• What patient history is most pertinent?

• Viral serologies– HAV IgM negative; HAV total +– HCV Ab +; HCV RNA negative– HBV core Ab Total +; HBV IgM equivocal– HBV s Ag +– HBV DNA 545,000

HBV and Immunosuppressed States : Chemotherapy and Corticosteroids

Weeks after Exposure

0 4 8 12 16 20 24 28 32 36 52 100

ChemoRx and/or

steroids

HBV DNA

IMMUNESUPPRESSION RECOVER

Acutehepatitis

ALT

IMMUNE REBOUND

Recovery of neutropenia or

steroid withdrawal

Natural History of HBV Reactivation During Chemotherapy

Acute liver

failure

Death

Chronic hepatitis

Cirrhosis

Reactivation of Hepatitis B Infection Among Cancer Patients

Large database from MD Anderson examined to determine HBV screening rates for patients who received chemotherapy

87 HBsAg-

1HBsAg+

anti-HBc-

25 HBsAg+ anti-HBc+

123HBsAg-

anti-HBc+ 2

anti-HBc+

2% of screened23% of positive

34HBV

Reactivation

70,737 new

patients

10,729 chemotherapy

1,787 screened

17% patients screened

1/5 with HBV risk screened

87

HBsAg

1,665 HBsAg and

anti-HBc

35 anti-HBc

Hwang JP, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 172.

Results of Prophylaxis or Treatment of 34 Patients with Reactivation

Fisher’s Exact Test, p<0.05

• Conclusion: Persons at risk for HBV are not being adequately screened prior to chemotherapy, resulting in preventable reactivation and mortality

Chemotherapy Reactivation

22%

72%71%

Hwang JP, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 172.

Patient and HBV status• Male, young age• Level of HBV-DNA >20,000 IU/ml• HBeAg positive• Active liver disease

Level of immunosuppression• Corticosteroids• Chemotherapy regimens : Vinca-alkaloid, anthracycline• Rituximab, infliximab• Immune reconstitutional periods• Bone marrow transplantation

Risk Factors of HBV Reactivation

Mindikoglu AL, Regev A, Schiff ER. Clin Gastroenterol Hepatol 2006;4:1076-81

Manzano-Alonso ML, Castellano-Tortajada G. World J Gastroenterol 2011;17:15-1537

Efficacy of Lamivudine Prophylaxis for Chemotherapy-Induced HBV Reactivation

9.2%

54%

8.7%

31%• Review of 10 RCTs &

prospective case series• Total N=173• LAM dose 100mg/D• AEs : LAM=placebo

%

Kohrt HE, Ouyang DL, Keefe EB. Aliment Pharmacol Ther 2006;24:1003-16

HBsAg negative

Anti-HBs ±Anti-HBc +

*Anti-HBs +Anti-HBc -

Anti-HBs -Anti-HBc -

HBV vaccination is recommended (double-dose ?)

Prior vaccination with appropriate

immune response

• Monitor HBV-DNA q 1-3 mo during and until 6 mo after immunosuppressive

Rx

• Antiviral prophylaxis, if HBV-DNA

positive Check anti-HBs at 1-2 mo after vaccination

*Anti-HBs+ is considered when titer ≥10 mIU/ml

HBV: Management of Patient Undergoing Immunosuppressive Therapy

Adapted from Bunchorntavakul C, Reddy KR. Medical treatment of hepatobiliary diseases associated with ulcerative colitis. In: Lichtenstein G. editor. Medical Therapy of Mucosal Ulcerative Colitis. Springer Publishing, New York, USA; 2012 [in press]

HBsAg positive

HBV: Management of Patient Undergoing Immunosuppressive Therapy

Adapted from Bunchorntavakul C, Reddy KR. Medical treatment of hepatobiliary diseases associated with ulcerative colitis. Springer Publishing. [in press] and Lok ASF, McMahon BF. AASLD Practice guideline 2009

HBV-DNA ≥2,000 IU/mlNormal or elevated ALT

HBV-DNA <2,000 IU/mlNormal ALT

• HBV treatment

• Delay immunosuppressive Rx until anti-HBV is initiated and HBV DNA negative

• Start antiviral prophylaxis before initiation of immunosuppressive Rx and continue for 6 mo

after discontinuing all immunosuppressive Rx (12 mo for rituximab)

• LAM can be used, if the anticipated Rx duration is <12 months

• ETV or TDF is preferred, if longer duration of Rx is anticipated

Case #3• 49 yr old male presents with self reported history of Hepatitis A,B,C• His only complaint is fatigue; referred by area health clinic• Exam notable for temporal muscle wasting; trace icterus, + fluid wave• He has high risk behaviors including IV drug use, multiple sexual

partners; “alcohol was never my thing”• Labs: T bil 2.1; AST 119; ALT 242; Albumin 3.0; AlkPhos 245; INR 1.3• You have no medical records or labs otherwise• You order “viral hepatitis panel”

• HCV Ab positive• HBV s Ag positive• HBV IgM negative

• Now what?• What is the likely hood this patient actually has chronic, active HBV

and HCV• What other co – infections should we screen for in ALL our patients?

HBV and HIV Co-infection

Prevalence of HBV-HIV co-infections by Geography and Route of Infection

Thio CL. Hepatology 2009;49:S138-S145

Liver-Related Mortality

01.7

0.8

14.2

0

5

10

15

20

HIV-/ HBV- HIV+/ HBV- HIV-/ HBV+ HIV+/ HBV+

Liver-related mortality rate(per 1,000 person-years)

Thio CL, et al. Lancet 2002;360:1921-6

• Multicenter prospective cohort study of 5293 men who had sex with men (in USA)

Influence of HIV on HBV• Lower rates of clearance of HBeAg• Increased serum HBV DNA viral load 1 • Reactivation of hepatitis in

asymptomatic carriers • Increased liver injury• Faster fibrosis cirrhosis and HCC• Higher mortality and morbidity

(1) Perillo RP, Regenstein FG, et al. Chronic hepatitis B in asymptomatic homosexual men with antibody to the human immunodeficiency virus. Ann Intern Med 1986:105:382-3

Influence of HBV on HIV

CONFLICTING DATA • Increased rate of HIV progression to AIDS ? 1 • No change in progression ? 2 • Cohort studies suggest that HBV does not

appear to influence the progression of HIV.

(1) Eskild A, Magnus P, et al. Hepatitis B antibodies in HIV-infected homosexual men are associated with more rapid progression to AIDS. Aids 1992:6:571-4(2) Diamondsstone LS, Blakly SA, et al. Prognostic factors for all-cause mortality among hemophiliacs infected with human immunodeficiency virus. Am J Epidemiol 1995:142:304-13

HBV and HIV TherapiesWild-type

HBVYMDD HBV HIV

Activity

Interferon (IFN) S S N

Lamivudine (LAM) S R Y

Adefovir (ADV) S S N*

Entecavir (ETV) S (0.5mg) S (1mg) Y

Emtricitabine (FTC) S R Y

Tenofovir (TDV) S S Y Telbivudine (LdT) S R N†

* ADV at dose 10mg/D has negligible activity against HIV (activity against HIV started at dose

30mg/D) † LdT has no activity against HIV, but should not be used in HIV/HBV co-infection because risk of selection of M204I mutation in YMDD motif of HIV

Not on HAART and treatment for both HIV and HBV in planned

HBV-DNA ↑, ALT ↑(Liver biopsy is considered in pt. with fluctuating or

mildly elevated ALT)

AASLD Practice Guideline 2009

Start antiviral Rx that is active against both viruses

(combination Rx is preferred)

Lamivudine or

Emtricitabine

+ Tenofovir

When HAART regimens are altered, drugs that are effective against HBV should not be discontinued without substituting another drug that has activity against HBV

Hepatitis D

26

3531

45

0

10

0

10

20

30

40

50

HDV-RNA negative ALT normalization

PEG-IFN + ADV

PEG-IFN

ADV

• RCT, 31 HDV patients• HBV-DNA levels decreased at wk 48 and rebounded at week 72 in all

patients

Pa

tient

s (%

)

Results at 72 weeks FU

Treatment of Hepatitis D: Peginterferon Versus Adefovir

P=0.006 P=0.004

P=0.02 P=0.003

Wedermayer H, et al. N Eng J Med 2011;364:322-31

HBV Decompensated Cirrhosis

Lamivudine significantly reduced the incidence of hepatic decompensation and HCC• Multicenter, DB-RCT in Asian populations, N=651

P=0.001 P=0.047

Liaw YF, et al. N Engl J Med 2004;351:1521-31

Entecavir and Tenofovir in Advanced Cirrhosis

70.5

87.8

72.7

57

76

55

6.74.4

9.1

2.2 2.20

0

20

40

60

80

100

HBV <400 cp/ml ALTnormalization

Tolerabilityfailure

Drug-relatedAEs

TDF

FTC/TDF

ETV

• DB-RCT, N=112• CTP and MELD scores improved in all groups

P=NS, across treatment groups

Tolerability failure = increased Cr ≥ 0.5 mg/dl from BL or serum phosphate <2 mg/dl x2 consecutive visit

% p

atie

nts

(at 4

8 w

ee

ks a

na

lysi

s)

Liaw YF, et al. Hepatology 2011;53:62-72

300 mg

0.5 or 1 mg

Summary & Curbside Thoughts

• Prenatal HBV screening does not always lend way to linkage to care• HBV monitoring during pregnancy and post pregnancy / life long

appropriate• Hepatitis B core – check it!• Chronic HBV infection (sAg+) and Chronic HCV infection (+RNA) rare

--- treatment paradigm will change in era of HCV DAAs for HCV• Delta screening – one time – for all; patients tend to have evidence of

advanced disease; low HBV DNA titers• Always treat HBV in HBV s Ag and clinical or histological evidence of

cirrhosis• Chronic HBV infection – a carcinogen!

– Yearly HCC surveillance at 40 for males; 50 for females– Earlier age surveillance if FHx HCC or African– If cirrhosis semi annual surveillance