Chronic Hepatitis Band Chronic Hepatitis c In

7/27/2019 Chronic Hepatitis Band Chronic Hepatitis c In

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Jeffrey C. Dunkelberg, MD, PhD

University of Iowa Health Care

I have no financial relationship(s) to disclose within the past12 months relevant to my presentation.

AND

My presentation does include discussion of off-label orinvestigational use.

Chronic Hepatitis

B and C

in Pregnancy

Jeffrey C. Dunkelberg, MD, PhD

Clinical Professor of Medicine

University of Iowa

HBV, HCV and Pregnancy

Maternal HBV or HCV infection increases:

preterm birth

low birth weight

premature rupture of membranes

gestational diabetes

congenital abnormalities

Key Points


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MTCT of HBV

- 5% with HBIG and HBV vaccine.

- Up to 30% with high HBV DNA levels

(>200,00 IU/mL).

Anti-viral treatment

for women with high HBV DNA levels

decreases MTCT of HBV.

HBV and Pregnancy

Key Points

MTCT of HCV occurs in 3-10% of pregnancies.

Risks for MTCT of HCV:

- high HCV RNA levels

- HIV-HCV co-infection

- PROM

- fetal monitoring with scalp electrode

No prophylactic measures prevent HCV MTCT.

HCV and Pregnancy

Key Points

Risks for Chronic Hepatitis B and C

Blood and blood product exposure

IVDU, inhaled drugs

transfusion before 1992

tattoos

Sexual activity

HBV

Perinatal transmission


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U.S. Prevalence of

Chronic HBV and HCV

HBV: 0.4%1 million Americans with chronic HBV

HCV: 1-2%4 million Americans with chronic HCV

Epidemiology

Prevalence of chronic HBV in pregnancy:

27-fold higher in Asians,

5-fold higher in African-Americans,

2-fold higher in Hispanics vs. whites.

HCV: more common in whites.

Higher incidence of HIV with HBV or HCV

Increased tobacco-, alcohol- and drug-abuse.

Connell, et al. 2011 Liver International

Reddick, et al. 2011 Journal Viral Hepatitis

Chronic Viral Hepatitis in Pregnancy

Pregnancy Outcomes with HBV and HCV

HBV and HCVPreterm birthLow birth weightPremature rupture of

membranes

Gestational diabetesCongenital anomalies

HCVCholestasis of pregnancyNICU admissionNeonatal abstinence syndrome

Connell, et al. 2011 Liver International

Safir, et al. 2010 Liver International

Berkley E, Leslie K, et al. 2008 Obstetrics and Gynecology


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HBV and HCV: Adverse Perinatal Outcomes

Maternal P value

Preterm Delivery (


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Diagnosis of Chronic HBV

HBsAg-positive

Immune-tolerant phase

Normal liver enzymes

Very high HBV DNA level

HBeAg +: marker of infectivity

Children, teens, young adults

Inactive HBV carrier

Normal liver enzymes

HBeAg -, HBeAb +

Undetectable or low HBV DNA

(< 1000 IU/mL)

Chronic active HBV

Abnormal liver enzymes

(ALT > 1.5 x normal, ALT > 30)

HBeAg +

HBV DNA > 20,000 IU/mL

Chronic Hepatitis B and Pregnancy


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Prevalence of HBV in Pregnancy

Varies by race and ethnicity:

Asian-Americans: 6%

African-Americans: 1%

Whites: 0.6%

Hispanics: 0.14%

Euler, et al. 2003 Pediatrics

Impact of Pregnancy on HBV

Pregnancy is well-tolerated.

HBV DNA levels do not change during pregnancy.

Hepatitis flare during pregnancy is uncommon.

HBV DNA levels decrease after delivery.

Soderstrom, et al. 2003 Scandinavian J Inf Dis

Rawal, et al. 1991 Am J Perinatology

HBV and Adverse Perinatal Outcome

Preterm

Birth

LBW


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Screening for HBV in Pregnancy

HBsAg + HBsAb -HBeAg

&

HBeAb

HBV DNALevel predicts MTCT

HBV

Vaccination

Pre - HBIG + HBV vaccine immunoprophylaxis era

10-40% rate of MTCT

90% MTCT with high HBV DNA and HBeAg-positive

With HBIG + HBV vaccine immunoprophylaxis

1-2% MTCT

5-10% MTCT if HBV DNA > 200,000 IU/mL

Mother-to-Child-Transmission of HBV

Alter, MJ. 2003 Journal of Hepatology

Del Canho, et al. 1994 Journal of Hepatology

Tovo, et al. 2005 Curr Opinion Inf Dis


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MTCT of HBV

Occurs in utero, intrapartum, or postpartum.

Intrauterine: probably uncommon.Threatened abortion

Amniocentesis: low-risk for MTCT of HBV (9 vs. 11%)

IntrapartumHigh efficacy of HBIG+vaccineMTCT occurs at or after birth.

Forceps or vacuum, no increase in risk.

No evidence that C-section prevents MTCT; not recommended.

PostpartumBreastfeeding is not a risk.

Ohto, et al. 1987 Jour Med Virol

Ko, et al. 1994 Arch Gynecol Obstet

Prevention of HBV Transmission by

HBIG + HBV Vaccine

No HBIG

or VaccineHBIG

HBIG +

HBV Vaccine

Infants without

HBV 5% 72% 95%

Ranger-Rogez 2004 Expert Rev Ant Infect Ther

HBIG + HBV Vaccination

5-10% failure of HBIG + HBV vaccine?

Failure to complete immunization

Failure to develop HBsAb (1-2%)

Mothers with > 100 million IU/mL HBV DNA

Su, et al. 2004 World Journ Gastro

MMWR. 2011

Pan, et al. 2012 Clinical Gastro Hepatol

Passive-Active Immunoprophylaxis

HBV

VaccineHBIG

HBIG +

HBV Vaccine

MTCT

of HBV26-36% 15-20% 5-10%


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Failure of HBIG + HBV Vaccine

High HBV DNA levels and HBeAg-positivity!8-32% rate of MTCT

Maternal HBV DNA level and MTCT of HBVHBV DNA < 107 IU/mL 0% transmission

HBV DNA > 107 IU/mL 32% transmission(del Canho)

HBeAg and MTCT of HBVHBeAg-negative1.5%

HBeAg-positive18%(Soleimani)

Del Canho, et al. 1994 Journ Hepatol; Soleimani, et al. 2010 Journal of Clinical Virology

Mother-To-Child-Transmission

Antiviral Therapy for HBV in Pregnancy

Lamivudine

Cytosine analogue, inhibits HBV DNA reverse transcriptase.

97% reduction in HBV DNA levels in 2 weeks.

Pregnancy Category C

Tenofovir (TDF)Current 1st-line treatment for HBV.

Pregnancy Category B

Safely used in 1731 pregnant women with HIV.No increase in birth defects.

Breastfeeding not recommended by manufacturers.

Lai, et al. 1998 NEJM

Pan, et al. 2012 Clinical Gastro and Hepatol

Keeffe, et al. 2008 Clinical Gastro and Hepatol

Lamivudine for HBV in Pregnancy

15 RCTs and 2 meta-analyses.Lamivudine reduces MTCT.Safe for mother and neonate.

2010 meta-analysis: 10 RCTs (Shi, et al.)13-24% decrease in MTCT of HBV with lamivudine

2011 meta-analysis: 15 RCTs, 1693 HBV-carrier mothers (Han)60-70% decrease in MTCT of HBV with lamivudine

Chinese RCT of lamivudine (Xu, et al.)100 mg/d beginning week 32.HBeAg-positive mothers with DNA > 200 million IU/mL

Significant reduction in MTCT: 18% vs. 39%

Shi, et al. 2010 Obstet and Gynecol; Han, et al. 2011 World Journal Gastroent;

Xu, et al. 2009 Journal of Viral Hepatitis


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Lamivudine in Pregnancy

Safety profile well-documented (Pan, 2012).

Antiviral Pregnancy Registry (APR)extensive experience shows safety

www.apregistry.com

No evidence of teratogenicity or adverse effects onpregnancy.

Consider for high HBV DNA level and HBeAg +mothers beginning at week 32.

Pan, et al. 2012 Clinical Gastro and Hepatol

Keefe, et al. 2008 Clinical Gastro and Hepatol

Birth Defect Rates By Trimester of Earliest Exposure to

Lamivudine, TDF Regimens and All ARV Regimens in APRa

EarliestExposureto ARVs

LAMRegimens

TDFRegimens

All ARVRegimens

1st

Trimester

Number ofDefects/

Live Births91/3089 14/606 126/4329

Prevalence(95% CI)

2.9%(2.4-3.6%)

2.3%(1.3-3.9%)

2.9%(2.4 - 3.5)

2nd/3rd

Trimester

Number ofDefects/

Live Births121/4631 5/336 145/5618

Prevalence(95% CI)

2.6%(2.2-3.1%)

1.5(0.5-3.4%)

2.6%(2.2 - 3.0)

aData collected January 1, 1989 July 31, 2008; APR interim report issued December 2008

CDC MACDP Birth Defect Rate = 2.72%


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APR Advisory Consensus Statementa

For the overall population exposed to antiretroviral

drugs in this Registry, no increases in risk of overall

birth defects or specific defects have been detected to

date when compared with observed rates for early

diagnoses in population-based birth defects

surveillance systems or with rates among those with

earliest exposure in the second or third trimester

aData collected January 1, 1989 July 31, 2008; APR interim report issued December 2008

Recommendations for Antiviral Therapy for

HBV-Infected Women Who Desire Pregnancy

Mild liver disease, low viremia (chronic inactive HBV)

Pregnancy before treatment

Moderate liver disease, no cirrhosis (chronic active HBV)

Treatment before pregnancy;

if responds, stop treatment before pregnancy

Advanced liver disease (advanced fibrosis-cirrhosis)Treatment before, during and after pregnancy

Mild liver disease, very high viremia (immunotolerant or CAH)Treatment in last trimester with a B category drug with post-partum discontinuation

EASL Clinical Practice Guidelines.

EASL Clinical Practice Guidelines. 2012 Journal of Hepatology; 57;167-185.

Pan, et al. 2012 Clin Gastro Hepat.

Pregnant Mothers with Positive HBsAg

HBV DNA > 200,000 IU/mL or

previous child failed HBIG + Vaccine

HBV DNA < 200,000 IU/mL, previous

child has successful prophylaxis

HBeAg (+)

HBV DNA >

200,000 IU/mL

High Risk for MTCT

Lamivudine or Tenofovir at the 3rd

trimester.(Consider elective C-section if DNA > 20 million IU/mL at full term.)

HBeAg (-)

HBV DNA 600,000 IU/mL)

HIV-HCV co-infection: increased 4-fold

HAART decreases risk

Prolonged rupture of membranes (> 6 hours)

Invasive fetal monitoring, scalp electrodes

C-section does not decrease risk of MTCT.

Yeung, et al. 2001 Hepatology

Ohto, et al. 1994 NEJM

Ferrero, et al. 2003 Acta Obstet Gynecol Scand

Mast, et al. 2005 Journ Infect Dis

Zanetti, et al. 1995 Lancet

Ghamar Chehreh, et al. 2011 Arch Gyn Obst

Breastfeeding is Safe

0/76 samples of breast milk contained HCV RNA.

Multiple studies show no MTCT with breastfeed.

American College of Obstetricians and AmericanAcademy of Pediatrics endorse breastfeeding by

mothers with HCV.

Vertical Transmission of HCV

Polywka, et al. 1999 Clinical Infect Dis

Kumar, et al. 1998 Journ of Hepatology

Resti, et al. 1998 BMJ

Thomas, et al. 1998 Int Journ Epidem

Diagnosis of HCV in the Newborn Early diagnosis requires PCR for HCV RNA.

May take 2-3 weeks for PCR to be positive.

Anti-HCV antibodies are passively transferred.

Maternal HCV-Ab can last to 12-15 months of life

Chronic HCV in the neonate

Detectable HCV-Ab at 18 months with a positivePCR for HCV RNA.

Positive PCR for HCV RNA at 3-6 months


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Postnatal Follow-up of Mothers

Pegylated interferon + Ribavirin +/- HCVprotease inhibitor combination therapy can lead

to a sustained viral response, a cure of chronic

hepatitis C, in 80% of patients.

Refer for treatment.

Keefe, et al. 2008 Clinical Gastro and Hepatol

Chronic Hepatitis Band Chronic Hepatitis c In

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