HBV Curbside consultation and case discussion in special populations
description
Transcript of HBV Curbside consultation and case discussion in special populations
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