S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

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Seminars in Perinatology

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Update on the management of B and C infections in the neonatal period

⁎ Claudia M. Espinosa, MD, MSca, and Ravi Jhaveri, MDb, aDivision of Pediatric Infectious Diseases, University of Louisville School of , Louisville, KY bDivision of Infectious Diseases, Department of , UNC School of Medicine, Campus Box 7231, Chapel Hill, NC 27599-7231 article info abstract

Keywords: Hepatitis B virus and hepatitis C virus have received a significant amount of attention in hepatitis b virus recent years, and both viruses share a significant amount of similarities with one another hepatitis c virus beyond just that they both primarily target the . In recent years, cases of both mother to child transmission infections have been fueled by a nationwide epidemic of injection drug use. Most relevant vaccine to this audience, they are both transmitted from mother to child. The increased cases in young adults combined with mother to child transmission translate into more exposed that will need to be managed and followed. Screening of pregnant women for hepatitis B infection coupled with appropriate treatment and prophylaxis measures are incredibly effective to preventing transmission. Prevention of hepatitis C infection is not yet possible, but advances in antiviral make interruption of transmission a future possibility. & 2018 Elsevier Inc. All rights reserved.

Introduction Hepatitis B virus

Hepatitis B virus (HBV) and hepatitis C virus (HCV) have Virology received a significant amount of attention in recent years, and both viruses share a significant amount of similarities HBV is a double-stranded DNA virus that is classified within with one another beyond just that they both primarily target the Hepadnavirus family.4 The major proteins produced the liver. In recent years, cases of both infections have been during infection are the surface antigen (HBsAg), the core fueled by a nationwide epidemic of injection drug use. Most antigen and the e antigen. Core and e antigens are formed relevant to this audience, they are both transmitted from from the same precursor pre-Core protein. The virus has two – mother to child (MTCT).1 3 The increased cases in young features to its lifecycle that are notable. First is that it forms a adults combined with MTCT translate into more exposed closed circular chromosome of DNA (cccDNA) that exists infants that will need to be managed and followed. This within the nucleus of an infected cell and serves as a review will summarize the relevant background of both HBV template for RNA transcription. This location is protected and HCV, review the clinical manifestations of each and from antiviral agents or cellular immune responses, so the rationale for screening and prevention and offer a glimpse cccDNA represents a sanctuary site where HBV infection can of what may be ahead in the future. A summary of the exist without external influences. Second is that HBV has an similarities and differences between the two viruses is RNA to DNA replication stage mediated by the viral polymer- presented in the Table. ase late in its lifecycle that is analogous to the reverse

⁎ Corresponding author. Tel.: þ1 919 962 4513; fax: þ1 919 962 4421. E-mail address: [email protected] (R. Jhaveri). https://doi.org/10.1053/j.semperi.2018.02.006 0146-0005/& 2018 Elsevier Inc. All rights reserved. 2 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

Table – Summary of similarities and differences of perinatal HBV and HCV infections.

HBV HCV

Pathogen Double stranded DNA Single stranded RNA Hepadnavirus Flaviviridae Genetic variability

Mode of transmission Bloodborne Bloodborne MTCT MTCT Sexual transmission Sexual transmission-MSM

Risk of chronicity after acute infection Low—adults High High—infants Risk of MTCT High (~90% if viral load high and HBeAg positive) Low (~6%) Screening in pregnancy Universal Risk-based Screening in newborn Post-vaccination titers 1-2 months after vaccine completion PCR RNA at 2–6 months HCV antibody at 18 months Treatment in pregnancy Antivirals available if high HBV DNA (4107 copies/ml or None available 4200,000 IU/ml) Treatment in neonate Post-exposure prophylaxis None available Vaccine HBIG

MTCT: mother to child transmission; MSM: men who have sex with men; HBIG hepatitis B immunoglobulin.

transcriptase of true retroviruses. This step is the reason why characterized by the lack of symptoms and normal liver many of the antivirals used against HBV are also used to treat enzymes, coupled with very high HBV DNA levels and the HIV infection. presence of the e antigen. The natural history of these children is that they stay in this phase for many years, and Transmission and epidemiology only in their late teenage or early adult years does their immune system begin to react to the virus. At this point is HBV is transmitted by bloodborne transmission, sexual trans- when they develop symptoms of more active hepatitis and mission and MTCT. Transmission via transfusion is exceed- when they become candidates for antiviral therapy. The ingly rare in the current era of widespread screening of the specific discussion of therapy is beyond the scope of this blood supply in the US, but this may not be true in resource- review. poor areas of the world. Screening of pregnant women for HBsAg, initiating prophylaxis for those that test positive and MTCT patterns and risk factors universal immunization have all served to reduce MTCT. Overall, cases of HBV had been dropping over the last Prior to any prophylaxis, studies showed that about 40% of 30 years in the US from over 200,000 cases per year in the infants became infected. What those studies also showed was 1980s to less than 38,000 by 2010.5 Over the last 5 years, cases that the more active disease a pregnant woman had, which at have been on the rise in many states driven by widespread the time was very high HBsAg levels, the higher the rate of injection drug use, contaminated needles and sexual trans- transmission.6 Early efforts used HBIG and then vaccine mission associated with drug use or drug seeking.1 independently, but a well-designed study looking combining – the two yielded 490% reduction in MTCT.7 9 As a result of this Clinical manifestations very high efficacy, the practice of administering HBIG and HBV vaccine within the first 12 hours of life has been the standard Infants infected with HBV in the neonatal period have very of care for many years. A recent study from the Centers for different outcomes than adults. While less than 10% of adults Disease Control and Prevention demonstrated that providers with HBV infection will progress to chronic infection, in the adhere to this standard more than 90% of the time.10 absence of any prophylaxis more than 90% of infants once However, the same study also showed that there is still a infected will have persistent detection of HBV surface antigen consistent subset of pregnant women for whom standard of on long-term follow up.6 Studies done prior to widespread care prophylaxis fails to protect against MTCT.10 These women prophylaxis showed that a minority of infants developed have the highest levels of HBV DNA (4107 copies/ml or severe hepatitis that could fulminate and even lead to death.7 4200,000 IU/ml) and they are e antigen positive. This has Because of these two important differences in infants, there been noted in several studies, and so efforts have been was a high priority placed on instituting preventive measures initiated to determine if using antiviral treatment in these against HBV MTCT. women to reduce their HBV DNA would be effective in In the current era, neonates that acquire HBV at birth addition to standard of care prophylaxis.11 Early studies used are most often asymptomatic. They enter a phase of the lamivudine, but the results were mixed due to low potency of infection that is called the “Immune Tolerant” phase. It is the drug and low barrier to resistance.12 More recent studies S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]] 3

have focused on using tenofovir, which has many advantages: blood transfusion safe practices, HCV infection rates an extensive history of being used to treat HIV-infected decreased for several years, but increase of cases has been pregnant women, a much higher potency agent and a much documented in association with the intravenous drug (IV) higher barrier to resistance. The studies using tenofovir epidemic. Recent data estimate that 2.5–4.7 million people in beginning at 28–32 weeks of gestation and continuing until the US population are chronically infected with HCV affecting 1–2 months post-partum have demonstrated reduced rates of mainly white young people living in rural areas.3,28 Repro- infants with transmission compared to those only receiving ductive age women have subsequently been affected, with a – standard of care prophylaxis.13 16 This practice is now part of disproportionate number of HCV cases among them and the American Association for the Study of Liver Diseases many more exposed infants.2,29 (AASLD) HBV guidelines for management of pregnant A recent study from the CDC calculates that the number of women.17 Real world studies have demonstrated that identi- reproductive-aged women with HCV infection had doubled fication of pregnant women at high risk for transmission can from 15,550 in 2006 to 31,039 in 2014, and estimated that be done and antiviral therapy can be used with high efficacy in almost 30,000 infected women gave birth about 1700 infected preventing transmission.18 Future efforts will need to focus on infants in 2014.30 However, those numbers are known to be expanding this practice so that all pregnant women with HBV an underestimation because of risk-based screening practices can enjoy the benefits or prevention and pre-emptive therapy. and lack of mandatory reporting to depart- ments. Several studies have suggested that risk-based Diagnosis of neonatal HBV infection screening during pregnancy will miss cases, and that univer- – sal screening can be cost effective.31 35 As in adults, the presence of surface antigen diagnoses an infected child. Surface antigen should not be measured Clinical manifestations within 1 month of hepatitis B vaccination to avoid confusion. An important reminder for practitioners seeing infants that While HCV chronically infected pregnant women are usually have received HBV prophylaxis with HBV vaccine and HBIG is asymptomatic, their infants are more likely to have compli- to re-evaluate the infants at 9–12 months for presence of HBV cations such as low birth weight, intrauterine growth retar- surface antibody and absence of HBV surface antigen. These dation, small for gestational age, late neonatal death, or 36–38 results confirm that the infant was protected, and many requiring neonatal intensive care. Similar to adults, children with breakthrough infection after prophylaxis are infants infected with HCV in the neonatal period are asymp- not detected for several years because follow up testing was tomatic. Some infants may have an early phase of elevated never performed. liver enzymes and high level viremia. Regardless of symp- toms, infants will spontaneously clear the infection at higher rates (25–50%) than adults (~15–25%).36,39 Hepatitis C virus MTCT patterns and risk factors Virology MTCT has been recognized as an important mode of infection HCV is a single stranded enveloped RNA virus that belongs shortly after the HCV was discovered. Yet the mechanisms of 19 to the Flaviviridae family. Six main genotypes have been infection remain unclear. Different series have reported a described and all can be transmitted to the mother to the wide range of transmission rates, but a recent meta-analysis infant. Within an infected individual, there also different viral including only studies using second or later generation tests genomes that evolve in response to immune pressure, a reported the risk of vertical HCV infection being 5.8% (95% CI: 19,20 phenomenon that is called “quasispecies”. This prodi- 4.2%–7.8%) among those born to HIV-negative women.40 Con- gious genetic variability contributes to the inability of the comitant infection with human immunodeficiency virus (HIV) host’s immune response to eliminate the virus and offers a was associated with increased risk of transmission in the major obstacle in the development of an effective vaccine. past, but currently, with highly active anti-retroviral therapy HCV specific T cell responses also may also impact persis- (HAART) available for HIV pregnant women the transmission tence of infection in those individuals unable to clear the risk has been estimated to be the same for infected and non- 21 – virus. For adults and children, the stronger the cellular infected women.41 44 Those findings are explained largely by 22 response the more likely the infection will resolve. HIV-induced immunosuppression in the absence of adequate viral control with subsequent higher HCV viral load.40 During Transmission and epidemiology pregnancy, most infected women have increased viremia followed by decreased viral load after delivery. The observa- The most common routes of HCV transmission in adults are tion that some women are able to spontaneously clear their unsafe healthcare procedures (in low resource settings) and HCV infection in the postpartum period has been attributed to injection drug use, whereas in children the main route of stronger T cell responses as well as favorable IL28B genetic – infection is MTCT.23 26 Sexual transmission can occur but is alleles.45,46 Although MTCT has been documented only in the primarily limited to men who have sex with men.27 In 2015, setting of maternal viremia, high viral load has been incon- approximately 71 million people in the world were infected sistently associated with vertical transmission.41,43,47,48 Other chronically with HCV and great variation of prevalence risk factors associated with MTCT included prolonged rupture within countries exist.25 In the US, after implementation of of membranes (46 hours), invasive fetal monitoring, 4 S EMINARS IN P ERINATOLOGY ] ( ]]]]) ]]]– ]]]

intrapartum contamination with infected secretions, and Treatment being born second in a twin delivery.40,41,48,49 In addition, the use of maternal intravenous drugs in the past or during The treatment of HCV infection in adults has evolved rapidly pregnancy and infection of peripheral blood mononuclear over the last few years. Rates of sustained virologic response cells have been associated with higher rate of MTCT due to (SVR) using DAAs surpass 95% and safety has not been an high viral heterogeneity related to repeated infections with issue transforming the paradigm of chronic infection into a different strains and quasispecies secondary to the use of “curable” infection. Many have asked if DAA therapy is now contaminated needles.43,44 On the other hand, mode of recommended for all children. Due to the lack of symptoms delivery (cesarean vs vaginal) and breastfeeding (unless the and higher spontaneous resolution in infants, no therapy will nipples are traumatized) have not been associated with ever be recommended before age 3. However, there is not increased risk of MTCT.41,47,50,51 treatment for neonates or infants as there are no biomarkers that identify which infants will clear the infection sponta- Diagnosis of neonatal HCV infection neously. DAA-based therapy is now FDA approved for chil- dren older than 12 years of age, clinical trials evaluating The Society for Maternal-Fetal Medicine (SMFM) recommends younger children and other DAA regimens are underway.56 It HCV testing for pregnant women who have risk factors at the is conceivable that with this additional data and cost reduc- first prenatal visit, and if negative, to repeat testing later in tions of the regimens that much more widespread treatment pregnancy if risk factors remain present. Also, they recom- recommendations for children. mend HCV-positive pregnant to be screened for other sex- ually transmitted diseases and counsel them against alcohol 52 consumption. Unlike hepatitis B, HCV treatment with new Summary direct-acting antiviral (DAAs) has not been studied assessing fi the tolerability or ef cacy in pregnant women. Therefore, Enormous advances on treatment of adult patients chroni- SMFM recommends that DAAs not be used outside the setting cally infected with HBV and HCV have occurred during the of a controlled clinical trial. Additionally, SMFM suggests last years, but little has been applied to infected pregnant counseling HCV positive women on the limited data on MTCT women and their infants. HBV infected women should be after prenatal invasive testing in case it is required, and evaluated and depending on the HBV DNA level, they should recommends providers to avoid internal fetal monitoring, be treated with antiviral therapy. All children born to mothers prolonged rupture of membranes, and episiotomy. Finally, with HBV should receive HBV vaccine and hepatitis B immu- they discourage cesarean delivery or avoiding breastfeeding noglobulin at birth. After completion of hepatitis B vaccine ’ 52 merely because of the mother s HCV infection. series, post-vaccination titers should be performed to ensure Being born to an HCV positive mother is a risk factor to they are protected. Many unanswered questions regarding acquire HCV infection, and those children should be eval- mechanism of MTCT and management of perinatally 53 uated. However, HCV antibody is not useful to identify exposed HCV children contribute to the lack of standardiza- infected neonates due to maternal transfer of antibodies. tion. Given the increase incidence of HCV infections, preg- Unfortunately, IgM antibodies are not available commercially nant women with risk factors should be screening actively and there are no studies evaluating their utility in predicting and that opportunity should be used to link those infected MTCT. For these reasons, nucleic acid testing (NAT) should be mothers to care after delivery as many of them will not be fi used during the rst months of life to evaluate exposed identified otherwise. Finally, there is room for improvement infants. The most common NAT used is quantitative real- in the management and follow up of perinatally infected time polymerase chain reaction (qRT-PCR), which has dem- children and strategies to change that paradigm will involve onstrated better sensitivity than other methods to detect low the collaborative work between obstetricians, pediatricians, 50 levels of viremia. The American Academy of Pediatrics neonatologists and health department authorities. (AAP) recommends antibody testing at 12–18 months when maternal antibodies should have cleared, but testing between 1 and 2 months with NAT is an alternative to earlier diagnosis Author disclosures and to decrease parental anxiety.50 There is little data to support the initial time frame for testing, and there are no Dr. Espinosa has no proprietary or commercial interest in any studies confirming the number of negative qRT-PCR needed product mentioned or concept discussed in this article. to rule out MTCT in those exposed infants. Some experts Dr. Jhaveri has received research funding from Gilead, recommend only one negative NAT and a non-reactive anti- Abbvie, and Merck. body after 12–18 months of age rule out infection, while 54,55 others recommend two NAT. There is general agreement references that NAT at 2–6 months is a reasonable time to test and may also limit the number of visits required. In real practice, the evaluation of HCV exposed neonates is challenging as long- 1. 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