Blood-Borne Viruses and Pregnancy. Prof Ashley Brown Imperial Healthcare NHS Trust

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1 Blood-Borne Viruses and Pregnancy Prof Ashley Brown Imperial Healthcare NHS Trust

2 Hepatitis B and Pregnancy

3 Global Prevalence of Chronic HBV Chronic HBV prevalence (% of population) Chronic HBV in the UK 3% < 2% - Low 2-7% - Intermediate > 8% - High Margolis et al, % 97% of people living with chronic HBV in the UK were born outside the UK (HPA statistics)

4 The cost of NOT treating HBV CIRRHOSIS TRANSPLANT HCC ASCITES VARICES

5 Maternal HBV is a growing problem in the UK A quarter of all babies born in the UK are the children of women born outside the UK many from areas of high HBV prevalence There were 200,000 births to immigrant mothers in Britain in in 10 of these children born in London - in some London boroughs more than 70% of babies are born to immigrant mothers Office for National Statistics

6 Hepatitis B On a global scale, mother-to-child transmission (MTCT) is by far the most important mode of transmission Hepatitis B remains one of the top 10 causes of death on the planet Identification of HBV positive mothers during antenatal screening allows Prevention of new cases of chronic infection in neonates Reduction of morbidity and mortality in mothers (long-term benefit to the child)

7 Transmission risk is related to maternal viral load In a cohort of 773 HBsAg positive mothers, 147 had persistently infected infants. Odds ratio higher in HBeAg positive mothers and those with HBV DNA level >3.9 X 10 8 copies/ml, (8 X 10 7 IU/mL) even if HBeAg negative (Burk RD, et al. J Infect Dis 1994;170: ). In 11,524 Indian women screened for HBV, 133 positive HBV. 66% babies had HBV DNA cord blood and 41% had serum markers positive. Maternal DNA >1.5 X10 5 copies/ml associated with intrauterine transmission. (Pande et al Abstract #252, presented at DDW 2008) Of a cohort of 313 chronically infected HBV positive women, 29% HBeAg positive and 68% HBV DNA positive. All babies received immunoprophylaxis. At 9 months, overall transmission rate was 2.9%. If maternal viremia >8 log 10, the perinatal transmission rate was 8.5% (Wiseman et al; AASLD 2008)

8 Stages of Chronic HBV

9 Vertical Transmission of BBV HBV/HCV may pass from mother to infant as a result of: Breast feeding In utero Intra partum

10 Transplacental Transmission Risk 402 HBsAg positive pregnant women 15/402 (3.7%) infants HBsAg positive within 24 hours 13/133 (9.8%) of HBeAg positive women intrauterine infection rate Placental pathology analysed for HBsAg, HBcAg, and HBV DNA Overall placental infection rate 44% Xu DZ et al. J Med Virol 2002;67:20.

11 HBV Outcome Depends on Age at Infection The risk of progression to chronic HBV infection is inversely proportional to the age at which the infection was acquired. Without immunoprophylaxis, up to 90% of infants born to hepatitis B e antigen (HBeAg)-positive mothers become HBV carriers. In comparison, 20% to 30% of children infected between age 1 year and 5 years, and fewer than 5% of immunocompetent adults, become HBV carriers These data underscore the need for early vaccination Birth 1 to 6 months 7 to 12 months 1 to 4 years Age at Infection Older Children & Adults Chronic infection % Symptomatic infection %

12 Without intervention the majority of children born to highly viraemic mothers will acquire HBV

13 A combination of active and passive immunisation can reduce that rate to less than 5%

14 EASL Guidelines The prevention of HBV perinatal transmission, which is considered to occur mainly at delivery, is traditionally based on the combination of passive and active immunisation with hepatitis B immunoglobulin (HBIg) and HBV vaccination. Such a strategy, however, may not be effective in a proportion of newborns from highly viremic (serum HBV DNA > IU/ml), mostly HBeAg positive, mothers, who carry a >10% risk of vertical HBV transmission despite HBIg and vaccination. Mothers with these high concentrations of HBV DNA should be informed that utilising a nucleos(t)ide analogue to reduce their viral loads has been shown to be safe and to reduce the risk of intrauterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIg and HBV vaccination.

15 How Safe and Effective is Vaccination? In large scale, international placebo-controlled trials vaccine alone has been shown to be 70-95% effective (compared to placebo of about 20%). The addition of HBIg increases this protection by about 10-15%. However, in the UK, (in the absence of routine immunisation), high-risk infants targeted - most studies reveal woeful completion rates for active immunisation

16 Antiviral Treatment during Pregnancy 8 women with HBV DNA>1.2x10 9 geq/ml treated with LAM 150 mg after 34wk vs 25 historical controls (all babies received standard prophylaxis)5/8 mothers dropped VL to <1.2x10 8 copies/ml 4/8 infants HBsAg +ve at 1 year (12.5%) compared to 7/24 (28%) born to controls No adverse events noted with lamivudine van Zonneveld M, et al. J Viral Hepat 2003;10:294-7

17 Lamivudine in late pregnancy to prevent perinatal transmission Double-blind, placebo-controlled study of 150 viraemic women (HBV DNA >1000 MEq/mL) randomized to LAM vs placebo from 32/40 All infants received vaccine +/- HBIg and were followed until wk 52 Infant Status at 1 year LAM (n=56) Placebo (n=59) P value HBsAg +ve 18% 39% HBV-DNA +ve 20% 46% Anti-HBs +ve 84% 61% High dropout rate (13% in the LAM + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) but no safety concerns were noted in LAM-treated mothers. Xu et al., J.Virol. Hep 2009; 16(2):94-103

18 Tenofovir in Pregnancy Retrospective Turkish study of 45 pregnant patients HBeAg+, HBV DNA levels > 10 7 copies/ml 21 received TDF 300 mg/d in third trimester, 24 served as controls All infants received 200 IU of HBIg within 24 hours of birth and HBV vaccine at 4, 8, and 24 wk. At week 28, none of the infants of TDFtreated mothers had immunoprophylaxis failure, compared to 8.3 % (2/24) of the infants of control mothers Celen et al., World J Gastroenterol Dec 28;19(48):

19 Safety of Tenofovir during pregnancy for the mother and fetus The use of TDF during pregnancy appears to be safe in terms of pregnancy outcomes, congenital anomaly risk, and other potential toxicities on neonates. In 6 studies of HIV+/-HBV-infected women receiving TDF during pregnancy, adverse events were mild to moderate; none were considered to be TDF-related. Five studies that followed in utero TDF-exposed infants showed no increased risk of growth or bone abnormalities. One study showed slightly lower infant height at age 1 year, but the significance is unclear. The Antiretroviral Pregnancy Registry database, with 1800 pregnancies exposed to TDF in the first trimester, does not indicate increased congenital anomaly risk with TDF exposure. Wang et al., Clin Infect Dis, 2013 Dec;57(12):

20 Breast-feeding & Antiviral Therapy for HBV Most clinicians advise women to continue TDF for three months post-delivery Breast-feeding is encouraged if woman if keen and able to do so Some evidence of trace amounts of drug present in breast milk, but overall benefits outway any theoretical risk Mirochnik et al, Antimicrob Agents Chemother 2009, 53(3):1170-6

21 EASL Guidelines The prevention of HBV perinatal transmission, which is considered to occur mainly at delivery, is traditionally based on the combination of passive and active immunisation with hepatitis B immunoglobulin (HBIg) and HBV vaccination. Such a strategy, however, may not be effective in a proportion of newborns from highly viremic (serum HBV DNA > IU/ml), mostly HBeAg positive, mothers, who carry a >10% risk of vertical HBV transmission despite HBIg and vaccination. Mothers with high concentrations of HBV DNA should be informed that utilising a nucleos(t)ide analogue to reduce their viral loads has been shown to be safe and to reduce the risk of intra-uterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIg and HBV vaccination.

22 HBV Antenatal Screening Protocol HBsAg tested as part of routine opt-out BBV Antenatal Screening Programme at booking NEG POS HBsAg neg No further action Specialist midwife gives positive result - counselling and advice LFT s, HBV-DNA, HBeAg, HCVAb, HDVAb, Review by Hepatologist Screening/vaccination of partner and other children HBV-DNA >10 6 OR HBeAg pos OR Previous MTCT Consider TDF in 3 rd Trimester HBIg at Birth High Risk Vaccination Schedule HBV-DNA<10 6 AND HBeAg neg AND Normal LFTs High Risk Vaccination Schedule Review of child to exclude vertical transmisson and vaccine response Long-term FU of mother, (including USS and Fibroscan)

23 HBV Antenatal Screening Protocol Education around the diagnosis of HBV Dispelling myths and rumours, explanation of natural history of HBV and need for long term follow-up. General liver health Testing of HBV-DNA (if not done prior to clinic) Assessment of liver health and exclusion of other chronic liver diseases including HDV Testing and/or referral of other household contacts Allows education and buy in from parents of strategies to minimise risk of vertical transmission to the baby Reinforcement of role of primary care in vaccination schedule Discuss follow-up of child

24 The New Hexavalent Vaccine All babies born on or after 1 August 2017 will receive a hexavalent (6 in 1) vaccine called Infanrix hexa for their primary immunisations at 8, 12 and 16 weeks This hexavalent vaccine includes hepatitis B (HepB) It also protects against diphtheria, tetanus, pertussis, poliomyelitis and disease caused by Haemophilus influenzae type b (Hib) Infanrix hexa will replace the pentavalent (5 in 1) infant vaccines Infanrix - IPV+Hib and Pediacel

25 HBV Neonatal Vaccination Schedule BIR 1 Mo 2 Mo 3 Mo 4 Mo 5 Mo 12 Mo Babies born to HBsAg +ve mothers prior to Aug 2017 Universal vaccination for all babies born from Aug 2017 Babies born to HBsAg +ve mothers prior to Aug 2017 HBV monovalent vaccine HBV monovalent vaccine + HBIg New hexavalent vaccine (inc HBV)

26 HBV Conclusions Risk of transmission is proportionate to maternal viral load and understanding virology underpins effective interventions to reduce transmission A healthy placenta is generally an effective barrier with the majority of transmission occurring intrapartum Exposed neonates are unlikely to clear infection and therefore early vaccination is essential Lowering viral load with TDF prior to delivery can reduce risk of transmission Screening can benefit both mother and child Long-term follow-up of mother is crucial

27 Hepatitis C and Pregnancy

28 Mother-child transmission of HCV Of a cohort of 15,250 pregnant women screened, 370 HCV antibody positive (transmission rate of 5.1%), - only mothers who were PCR+ transmitted Conte et al, Hepatology 2000 Risk greater if maternal viral load >10 7 copies/ml, in acute infection, HIV coinfection, prolonged rupture of membranes or instrumental delivery Dal Molin et al, J Med Virol 2002;67:

29 Antenatal Screening for HCV Current guidelines do NOT recommend universal screening for HCV except in: Women with a history of IVDU Women may not declare past history IVDU is not the only drug-related risk factor Women born in countries of high HCV prevalence Midwives do not have necessary time or knowledge Low prevalence does not mean low risk

30 Arguments For and Against Antenatal Screening for HCV AGAINST UK is not a high prevalence country for HCV No suitable intervention in pregnancy Not cost-effective Not a major priority FOR Prevalence in ANC at SMH >1% Changing immigration patterns Birth rates higher in immigrant populations Trials underway of DAA s in third trimester Elimination post-delivery prevents transmission in subsequent pregnancies Simply not true! But what about the WHO declaration?

31 Current management of the HCV-exposed infant No contraindication to breast-feeding Consider high-risk HBV vaccination schedule depending on household risk Optional diagnostic HCV PCR at 6w to 3m Definitive HCVAb at 14-18m Infected children should be followed by an appropriate specialist with assessment of disease progression and offer of treatment at the appropriate time Mother should be offered anti-hcv treatment before next pregnancy (short duration, IFN-free, highly efficacious)

32 Hepatitis E and Pregnancy

33 Epidemiology of HEV Epidemic and sporadic acute hepatitis through faeco-oral trasmission (water) with incubation 2-6 weeks Genotypes 1 & 2 (Asia, Middle East, Africa) may cause FHF in pregnant women with a short preencephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation Genotypes 3 & 4 (Europe, N America, Mexico, Egypt) do not appear to have different clinical course in pregnant women *Saeedi MI et al. J Coll Physicians Surg Pak Sep;14(9):527-9

34 Clinical Features Diagnosed on clinical suspicion and relevant travel history Elevated transaminases +/- bilirubin Positive HEV IgMAb Confirmatory HEV-RNA In the majority of men and non-pregnant women it is a mild, self limiting illness with low fatality It can progress to chronic infection in the elderly or immunosuppressed Kashmir epidemic Incidence HEV (%) Incidence FHF (%) Men Non-pregnant women Pregnant 1 st trimester nd trimester rd trimester Khuroo MS et al. Am J Med 1981; 70:252-5

35 Pregnancy risks of HEV Complication Fulminant hepatic failure (FHF) (6-7x higher cf non-pregnant) 33-66% HEV Viral Load* (μl/ml) Acute infection FHF Maternal mortality (all have FHF) 27-33% Preterm delivery 66-90% Non-pregnant Pregnant Vertical transmission* 33% Fetal loss* 29-66% Risks thought to be greater in pregnancy (esp 3 rd trimester) due to reduced cell-mediated immunity and increased endogenous steroids increasing viral replication May be exacerbated by maternal malnutrition and folate deficiency Neonatal infection can result in hypoglycaemia and hepatic necrosis Khuroo MS et al. J Vir Hep 2003; Kumar A et al. Int J Obs Gyn 2004; Patra S et al. Ann Int Med 2007; Kar P et al. Am J Gastroenterol Oct 2008;103:

36 Management of HEV in pregnancy Continue all supportive measures as with non- pregnant Antibiotics for secondary infection Maintain hydration and prevent hypoglycaemia FFP, blood products for coagulopath Fetal monitoring If any suggestion of FHF, mother should be transferred to a liver transplant unit Unclear whether early delivery improves survival Small retrospective study showed improved survival if excluded grade 4 encephalopathy but urgent need for RCT Immune globulin available in India for locally prevalent genotypes Vaccine against Hepatitis E genotype 1 Safe water supply Banait VS et al. Ind Soc Gastroenterol 2007;26:6-10 Arankalle VA et al. J Viral Hepat 1998; 5:

37 Thank You