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

Disclosures Viral Hepatitis in Pregnancy  Grant Support – Zydus Pharmaceuticals Monika Sarkar, MD, MAS Associate Professor of Medicine Division of GI/Hepatology, UCSF  No relevant disclosures to this talk October 17 th , 2019 1 2 1 2 HBV & HCV in Pregnancy- What an OB Provider Should Know  Epidemiology in reproductive-aged women Hepatitis C in Pregnancy  Risk factors for maternal to child transmission  Associated obstetric and perinatal risks  Management in pregnancy 3 4 3 4

Rate of HCV in pregnant women Epidemiology of HCV in per/1,000 live births- 2014 Reproductive-Aged Women  364% increase in acute HCV from 2006-2012 among those aged < 30 in southeast U.S. (KY, TN, WV, VA) 1 Doubled since 2009  Rising number of reproductive aged women with HCV, and babies receiving HCV testing 3 Zibbell et al,. CDC MMWR Morb Mortal Wkly Rep 2015; Esmaeili et al, Journal of Viral Hep, 2017 Patrick et al, CDC MMWR May 12, 2017 / 66(18);470–473 Koneru et al, CDC MMWR Morb Mortal Wkly Rep 2016 5 6 5 6 HCV Screening in Pregnancy 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) Risk-Based Universal (n=10,420) (n=9033) % Screened 18% 100% HCV Ab + 4.3% 4.9% HCV RNA performed 54% 100% HCV RNA + (active infxn) 1.7% 3.4% Rose M, Myers J, et al, Hughes et al, Am J Obstet Gynecol 2017 AASLD 2019 Abstract #87 7 8 7 8

Universal Screening is Cost Effective Universal Screening is Cost Effective  Markov model to evaluate cost effectiveness of Cost effective if prevalence > 0.05% HCV screening ( lowest state prevalence = 0.06% in Hawaii  Assumed prevalence of HCV at 0.7% based on national data  Models incorporated fibrosis stages Chaillon A et al, Clinical Infectious Diseases, 2019 Chaillon A et al, Clinical Infectious Diseases, 2019 9 10 9 10 Universal HCV Screening in Pregnancy Does HCV Affect Fertility?  Probably doesn’t decrease female fertility in absence of - Recommended by cirrhosis the IDSA and AASLD  Sperm count & motility decreased in men with HCV vs uninfected controls  For couples seeking assisted reproductive technology - UCSF now instituting universal screening (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 11 12 11 12

Mother-to-Child Transmission of HCV Risk to Baby Potential Mechanisms  Antenatal (up to 30%)  Trans-placental  Prevalence of MTCT  Amniocentesis  HCV infection and perinatal health  Peri-Partum (majority)  Vaginal exposure during delivery  Postnatal (rare) 13 14 13 14 Risk of HCV MTCT Factors Linked with Risk of MTCT- Mode of Delivery N=244 mothers, 8 HIV+ 25 25 N=1080 mothers, 177 HIV+ 20 Studies Strength of 20 Variable Summary of Findings # women Evidence Elective c-section vs. 4 cohort studies, Low No difference, but trends in 15 15 vaginal delivery N=2080 opposite directions in highest quality studies 10 10 C-section vs. vaginal 11 cohort studies, Moderate No association delivery N=2308 5 5 0 0 HIV neg HIV pos HIV neg HIV pos Rac M et al, Obstet Gynecol Clin North Am 2014 Cottrell E et al, Ann Intern Med 2013 Dore GJ. BMJ. 1997;315(7104):333-7. Mast EE, J Infect Dis 2005;192:1880-9 15 16 15 16

Factors Linked with Risk of MTCT Factors Linked with Risk of MTCT  Post-partum Breastfeeding 14 cohort Moderate No association studies, 2971 Studies Strength of Variable Summary of Findings European Study- # women Evidence US Study Italy/Spain/German/Ireland/Scotland/ Invasive fetal 3 cohort studies, Insufficient Inconsistent but one good Breastfed Belgium/Sweden monitoring vs none N=928 quality study OR=6.7 (95% CI Not Breastfed 1.1-36) 5  OR = 0.92 (0.50.1.70), adjusted for 4.2 sex, prematurity and mode of Prolonged rupture of 2 cohort studies, Low Yes with >6 hrs having 4 delivery membranes vs. none N=245 OR=9.3 (95% CI 1.5-180) 3.2 3 - Amniocentesis does not appear to increase risk, but data limited 2 - One study found association with episiotomy 1 2 5 62 120 0 Rac M et al, Obstet Gynecol Clin North Am 2014, Infant Infected Cottrell E et al, Ann Intern Med 2013, Gagnon et al J Obstet Gynaecol Can 2014, Cottrell E, Ann Intern Med 2013;158(2):109-13 European Paediatric Hepatitis C Virus Network J Infect Dis. 2005;192:1872-9. Garcia-Tejedor et al, Euro J Obstet Gynecol Repro Biol 2015 Mast EE, J Infect Dis. 2005;192:1880-9 17 18 17 18 Lack of Follow-up Testing of Infants Outcomes of Infants With Born to HCV Positive Mothers HCV Infection - Infants may have + HCV Ab from mom up to 18 months 2011-13 - Can screen by HCV RNA x 2 > 1 month after delivery  MTCT is most common  80% infected neonates develop chronic infection mode of HCV acquisition  Adverse fetal outcomes: in children ?? Due to maternal  Increased congenital anomalies  Lack of follow-up testing health or exposures (opiates, other  Low birth weight /small for gestational age in children is missed drugs) vs HCV opportunity for case  Adverse neurologic outcomes (16%) (84%) identification/treatment *Followed for up to 20 months post-birth Huang et al, Medicine 2016; Reddick et al, JVH 2011 Kuncio DE, Clin Infect Dis 2016 19 20 19 20

Does Pregnancy Opportunities to Reduce Mother To Affect Natural History of HCV? Child Transmission (MTCT)  Plan pregnancy and treat mother before  Pregnancy = “ altered immunological state ” conception- YES  HCV Flare during pregnancy?  Serum aminotransferase levels decrease during pregnancy and rebound in post-partum period 1,2  Unclear if alters disease progression 3  Reported associations with:  Intrahepatic cholestasis of pregnancy (up to 20%)  Gestational diabetes Mother Baby 1 Conte D. Hepatol. 2000 Mar;31(3):751-5. 2 Paternoster DM. Am J Gastroenterol. 2001 Sep;96(9):2751-4. 3 Fontaine 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. 21 22 21 22 Opportunities to Reduce Mother To HCV-Infected Women Planning Pregnancy Child Transmission (MTCT)  Prioritized by most insurance companies  Continue treatment in women who conceive  High efficacy of current DAA therapies while on treatment?  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 Mother Baby IDSA-AASLD HCV Guidance 2016 23 24 23 24

DAA Safety in Pregnancy DAA Continuation in Pregnancy  If DAA combination includes ribavirin:  None FDA approved for use during pregnancy  Stop RBV immediately  Ribavirin is still part of some treatment regimens  Counseling regarding termination of pregnancy  Highly teratogenic  If DAA combination does not include ribavirin  No pregnancy (in riba exposed sperm or eggs) for at least  Weigh risks and benefits to mother versus infant 6 (prefer 12) months after use  Situations that may favor continued treatment:  HIV coinfected mother?  Mother with cirrhosis or extrahepatic manifestations of HCV (MPGN) 1.American Society for Reproductive Medicine Guidelines, Fertility Sterility; 340-346, 2013 25 26 25 26 Safety of HCV Antivirals in Pregnancy Opportunities to Reduce Mother To Child Transmission (MTCT)  Phase 1 trial of 12 weeks of ledipasvir/sofosbuvir  Initiate treatment in third trimester???  Pregnant women, HCV-mono-infected, no cirrhosis, genotypes EMERGING DATA… 1,4,5,6  Initiated at weeks 23-24 Mother Baby Chappell et al, CROI 2019, Abstract #87 27 28 27 28

Safety of HCV Antivirals in Pregnancy Caveats to Third Trimester Treatment  n=29 screened (n=10 genotypes 2&3)  Not FDA approved- more data needed  Well tolerated (AEs only grade 1 or 2)  Not for genotypes 2 and 3  May not prevent all MTCT (1/3 in utero events)  8/8 women who completed 12 wks of treatment achieved SVR  Children can be treated as early as 3 years of age  No infant-related side effects  5/9 infants completed 1 year f/u: None had HCV infection Chappell et al, CROI 2019, Abstract #87 29 30 29 30 Impact of Immigration on US HBV Prevalence Globally, 65 million reproductive-aged women are HBV-infected >3.6 million Asians Hepatitis B in Pregnancy ~ 900,,000 South Americans HBsAg Prevalence [2] ≥ 8% (high) >800,00 2% to 7% (intermediate) Africans < 2% (low) 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 31 32 31 32