[PPT] - Viral Hepatitis in Pregnancy Grant Support Zydus Pharmaceuticals PowerPoint Presentation

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Viral Hepatitis in Pregnancy

Monika Sarkar, MD, MAS Associate Professor of Medicine Division of GI/Hepatology, UCSF October 17th, 2019

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Disclosures

Grant Support – Zydus Pharmaceuticals
No relevant disclosures to this talk

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HBV & HCV in Pregnancy- What an OB Provider Should Know

Epidemiology in reproductive-aged women
Risk factors for maternal to child transmission
Associated obstetric and perinatal risks
Management in pregnancy

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Hepatitis C in Pregnancy

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Epidemiology of HCV in Reproductive-Aged Women

364% increase in acute

HCV from 2006-2012 among those aged < 30 in southeast U.S. (KY, TN, WV, VA)1

Rising number of

reproductive aged women with HCV, and babies receiving HCV testing3

Zibbell et al,. CDC MMWR Morb Mortal Wkly Rep 2015; Esmaeili et al, Journal of Viral Hep, 2017 Koneru et al, CDC MMWR Morb Mortal Wkly Rep 2016

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Rate of HCV in pregnant women per/1,000 live births- 2014

Patrick et al, CDC MMWR May 12, 2017 / 66(18);470–473

Doubled since 2009

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HCV Screening in Pregnancy

Hughes et al, Am J Obstet Gynecol 2017

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Risk-Based vs Universal Screening

Retrospective study of n=19,453 pregnant women in KY
Compared periods of risk-based (5/2014-12/2015) to

universal HCV screening (5/2016-12/2017)

Rose M, Myers J, et al, AASLD 2019 Abstract #87

Risk-Based (n=10,420) Universal (n=9033) % Screened 18% 100% HCV Ab + 4.3% 4.9% HCV RNA performed 54% 100% HCV RNA + (active infxn) 1.7% 3.4%

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Universal Screening is Cost Effective

Markov model to evaluate cost effectiveness of

HCV screening

Assumed prevalence of HCV at 0.7% based on

national data

Models incorporated fibrosis stages

Chaillon A et al, Clinical Infectious Diseases, 2019

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Universal Screening is Cost Effective

Chaillon A et al, Clinical Infectious Diseases, 2019

Cost effective if prevalence > 0.05%

(lowest state prevalence = 0.06% in Hawaii

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Universal HCV Screening in Pregnancy

Recommended by

the IDSA and AASLD

UCSF now instituting universal screening

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Does HCV Affect Fertility?

Probably doesn’t decrease female fertility in absence of

cirrhosis

Sperm count & motility decreased in men with HCV vs

uninfected controls

For couples seeking assisted reproductive technology

(ART) outcomes no different if men HCV infected

Sperm washing for IUI/IVF eliminates virus from the

sample

Safarinejad et al, British Journal of Urology 2010; Yang et al, Int J Clin Exp Med 2015; Pasquier et al, AIDS 2000

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Risk to Baby

Prevalence of MTCT
HCV infection and perinatal health

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Mother-to-Child Transmission of HCV Potential Mechanisms

Antenatal (up to 30%)
Trans-placental
Amniocentesis
Peri-Partum (majority)
Vaginal exposure during delivery
Postnatal (rare)

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Risk of HCV MTCT

5 10 15 20 25 HIV neg HIV pos N=1080 mothers, 177 HIV+

Dore GJ. BMJ. 1997;315(7104):333-7.

5 10 15 20 25 HIV neg HIV pos N=244 mothers, 8 HIV+

Mast EE, J Infect Dis 2005;192:1880-9

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Factors Linked with Risk of MTCT- Mode of Delivery

Variable Studies # women Strength of Evidence Summary of Findings Elective c-section vs. vaginal delivery 4 cohort studies, N=2080 Low No difference, but trends in

pposite directions in

highest quality studies C-section vs. vaginal delivery 11 cohort studies, N=2308 Moderate No association

Rac M et al, Obstet Gynecol Clin North Am 2014 Cottrell E et al, Ann Intern Med 2013

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Factors Linked with Risk of MTCT

Variable Studies # women Strength of Evidence Summary of Findings Invasive fetal monitoring vs none 3 cohort studies, N=928 Insufficient Inconsistent but one good quality study OR=6.7 (95% CI 1.1-36) Prolonged rupture of membranes vs. none 2 cohort studies, N=245 Low Yes with >6 hrs having OR=9.3 (95% CI 1.5-180)

Rac M et al, Obstet Gynecol Clin North Am 2014, Cottrell E et al, Ann Intern Med 2013, Gagnon et al J Obstet Gynaecol Can 2014, Garcia-Tejedor et al, Euro J Obstet Gynecol Repro Biol 2015

Amniocentesis does not appear to increase risk, but data limited
One study found association with episiotomy

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Factors Linked with Risk of MTCT

Post-partum

Breastfeeding 14 cohort studies, 2971 Moderate No association

Cottrell E, Ann Intern Med 2013;158(2):109-13 European Paediatric Hepatitis C Virus Network J Infect Dis. 2005;192:1872-9. Mast EE, J Infect Dis. 2005;192:1880-9

3.2 4.2 1 2 3 4 5 Infant Infected Breastfed Not Breastfed European Study-

Italy/Spain/German/Ireland/Scotland/ Belgium/Sweden

OR = 0.92 (0.50.1.70), adjusted for

sex, prematurity and mode of delivery

US Study

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Outcomes of Infants With HCV Infection

80% infected neonates develop chronic infection
Adverse fetal outcomes:
Increased congenital anomalies
Low birth weight /small for gestational age
Adverse neurologic outcomes

?? Due to maternal health or exposures (opiates, other drugs) vs HCV

Infants may have + HCV Ab from mom up to 18 months
Can screen by HCV RNA x 2 > 1 month after delivery

Huang et al, Medicine 2016; Reddick et al, JVH 2011

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Lack of Follow-up Testing of Infants Born to HCV Positive Mothers

MTCT is most common

mode of HCV acquisition in children

Lack of follow-up testing

in children is missed

pportunity for case

identification/treatment

(16%)

2011-13

*Followed for up to 20 months post-birth

Kuncio DE, Clin Infect Dis 2016

(84%)

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Does Pregnancy Affect Natural History of HCV?

Pregnancy = “altered immunological state”
HCV Flare during pregnancy?
Serum aminotransferase levels decrease during

pregnancy and rebound in post-partum period1,2

Unclear if alters disease progression3
Reported associations with:
Intrahepatic cholestasis of pregnancy (up to 20%)
Gestational diabetes

1Conte D. Hepatol. 2000 Mar;31(3):751-5. 2Paternoster DM. Am J Gastroenterol. 2001 Sep;96(9):2751-4. 3Fontaine H et al. Lancet 2000 Oct 14;356(9238):1328-9.

Aebi-Popp. J of Virus Eradication 2016; 2: 52-54. Rac et al. Obstetrics and gynecol clinics of North America 2014;41 (4): 573-592.

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Opportunities to Reduce Mother To Child Transmission (MTCT)

Plan pregnancy and treat mother before

conception- YES

Mother Baby

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HCV-Infected Women Planning Pregnancy

Prioritized by most insurance companies
High efficacy of current DAA therapies
Viral eradication in ≥95% (slightly lower if cirrhosis)
Short treatment as few as 4 weeks for some women

(younger women more likely to have low stage of fibrosis)

Excellent safety and tolerability
Caveats
Avoid RBV, need (6)-12 month period of “washout” post-

treatment before conceiving

Variable access in some states if low stage of fibrosis

IDSA-AASLD HCV Guidance 2016

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Opportunities to Reduce Mother To Child Transmission (MTCT)

Continue treatment in women who conceive

while on treatment?

Mother Baby

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DAA Safety in Pregnancy

None FDA approved for use during pregnancy
Ribavirin is still part of some treatment regimens
Highly teratogenic
No pregnancy (in riba exposed sperm or eggs) for at least

6 (prefer 12) months after use

1.American Society for Reproductive Medicine Guidelines, Fertility Sterility; 340-346, 2013

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If DAA combination includes ribavirin:
Stop RBV immediately
Counseling regarding termination of pregnancy
If DAA combination does not include ribavirin
Weigh risks and benefits to mother versus infant
Situations that may favor continued treatment:
HIV coinfected mother?
Mother with cirrhosis or extrahepatic manifestations of HCV (MPGN)

DAA Continuation in Pregnancy

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Opportunities to Reduce Mother To Child Transmission (MTCT)

Initiate treatment in third trimester???

EMERGING DATA…

Mother Baby

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Safety of HCV Antivirals in Pregnancy

Phase 1 trial of 12 weeks of ledipasvir/sofosbuvir
Pregnant women, HCV-mono-infected, no cirrhosis, genotypes

1,4,5,6

Initiated at weeks 23-24

Chappell et al, CROI 2019, Abstract #87

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Safety of HCV Antivirals in Pregnancy

n=29 screened (n=10 genotypes 2&3)
Well tolerated (AEs only grade 1 or 2)
8/8 women who completed 12 wks of

treatment achieved SVR

No infant-related side effects
5/9 infants completed 1 year f/u: None

had HCV infection

Chappell et al, CROI 2019, Abstract #87

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Caveats to Third Trimester Treatment

Not FDA approved- more data needed
Not for genotypes 2 and 3
May not prevent all MTCT (1/3 in utero events)
Children can be treated as early as 3 years of age

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Hepatitis B in Pregnancy

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Impact of Immigration on US HBV Prevalence

HBsAg Prevalence[2] ≥ 8% (high) 2% to 7% (intermediate) < 2% (low) >3.6 million Asians ~ 900,,000 South Americans >800,00 Africans

World Health Organization. WHO global health sector strategy on viral hepatitis, 2016-2021 US Department of Homeland Security 2009. Weinbaum CM, et al. MMWR Recomm Rep. 2008

Globally, 65 million reproductive-aged women are HBV-infected

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Natural History of HBV Exposure

95% of adults clear acute HBV
But ~90% of exposed infants develop chronic HBV
Perinatal transmission accounts for 50% of the global

burden of chronic HBV

Transmission usually occurs at time of delivery with

exposure to maternal blood and secretions- less commonly in utero transmission

World Health Organization. WHO global health sector strategy on viral hepatitis, 2016-2021 ; Terrault et al, AASLD Guidelines Hepatology 2018

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Risk Factors for MTCT of Hepatitis B

Invasive procedures- Limited data. Amniocentesis shown

to increase transmission risk in moms with viral load > 10 million1

Vaginal vs c-section: Conflicting data. Advise mode of

delivery per obstetric indications, NOT HBV status2,3

Breastfeeding does not increase transmission3,4
HBV DNA > 200,000 IU/ml= Only well established risk

factor for MTCT 5,6

1. Yi et al, J Hepatology 2014; 2.Chen et al Midwifery 2019; 3. Dionne-Odom et al, SFMFM

Guideline, Am J Obstet Gynecol 2016; 4. Pirillo et al, JVH 2015 5. Liu et al, Hepatol Research 2016; 6. Zou et al, JVH 2012

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Lab Test What It’s Assessing

HBsAg Active infection (chronic or acute) HBcIgM Acute infection HBcIgG Exposure (cleared or chronic infxn) HBsAb Immunity (from cleared infxn or vaccine) HBeAg/HBeAb Immune state of active HBV that guides treatment thresholds HBV DNA Level of viremia ALT HBV disease activity (liver inflammation)

*False positive HBsAg uncommon in healthy patients, unless within 2-3 weeks of HBV vaccination

What to order if positive HBsAg on pre-natal labs?

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Mother to Child Transmission (MTCT) of HBV

MTCT is reduced with passive/active immunization
Fails in 10-30% of infants of highly viremic moms
Third trimester antiviral therapy reduces MTCT to 0-3%

(rare transmission via placenta)

Tan et al. J Viral Hep 2016; Pan et al. NEJM 2016

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Safe Antivirals In Pregnancy

Antiviral Resistance Risk of birth defects Rate of maternal-to- child transmission

Lamivudine

 No increased risk 3%

Telbivudine

 0%

Tenofovir (TDF)

None reported 0%

Terrault et al, AASLD Guidelines Hepatology 2018; Dionne-Odom et al, SFMFM Guideline, Am J Obstet Gynecol 2016; LACTMED 2019

TDF is first line for treatment in pregnancy- Not contraindicated in breastfeeding

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Pregnancy Associated Flares

Kushner T and Sarkar, M Clinical Liver Diseases, 2018

6-14% during pregnancy
10-50% post-partum
Usually mild and self limited

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HBsAg-Positive Mother

Elevated ALT No Yes Test HBV DNA between weeks 26-28 Hepatology referral HBV DNA  200,000 IU/mL HBV DNA < 200,000 IU/mL ALT 3 months postpartum Initiate TDF between weeks 28-32* *Favor starting at 28 weeks to ensure sufficient time for viral load decline prior to delivery TDF, tenofovir disoproxil fumarate; Stop TDF at delivery

Adapted from Kushner T & Sarkar M, Clinical Liver Diseases 2018

HBsAg-Positive Mother

Elevated ALT No Yes Test HBV DNA between weeks 26-28 Hepatology referral HBV DNA  200,000 IU/mL HBV DNA < 200,000 IU/mL ALT 3 months postpartum Initiate TDF between weeks 28-32*

*Favor starting at 28 weeks to ensure sufficient time for viral load decline prior to delivery TDF, tenofovir disoproxil fumarate;

Stop TDF at delivery

Adapted from Kushner T & Sarkar M, Clinical Liver Diseases 2018 May need antiviral treatment now

Refer ALL to GI/hepatology

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Improving Linkage With Care

Refer ALL women with HBV to GI/liver clinic:

Determine whether mom needs third trimester

treatment to prevent MTCT

Discuss medication safety in pregnancy and

breastfeeding

Leverage perinatal care to link mom with lifelong

HBV care…

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Linkage With GI/Hepatology Care

To assess whether mother’s liver disease activity

warrants treatment now

Initiate liver cancer screening when appropriate (i.e.

family history of liver cancer would prompt screening now)

Determine baseline severity of fibrosis (we have non-

invasive imaging tests in clinic)

Ensure family members and partners screened
…HBV is dynamic disease with need for LIFELONG

laboratory monitoring every 6 months to assess for disease progression and need to start therapy

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Summary- HBV in Pregnancy

Maternal and perinatal outcomes favorable- MTCT

transmission is primary risk

HBV DNA > 200,000 IU/ml increases MTCT
Tenofovir (TDF) is first-line treatment in pregnancy
HBV status should not guide mode of delivery
TDF is not contraindicated in breastfeeding
Pregnancy is opportune time to link moms with lifelong

HBV care

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Summary- HCV in Pregnancy

Rising HCV in pregnancy
Universal HCV screening is cost effective
MTCT occurs in ~5% of children
Increased risk of MTCT: HIV, PROM > 6 hrs, invasive

fetal monitoring, episiotomy

HCV status should not guide mode of delivery
Breastfeeding safe, avoid if skin breakdown
Prioritize HCV cure before conception…emerging data
n drug safety in pregnancy