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Worldwide, chronic hepatitis B virus (HBV) remains a leading cause of cirrhosis and liver cancer. Prevention of transmission and thereby chronic infection is considered the most effective public health intervention to minimize the global burden of HBV and its disease-related complications. Despite vaccination, mother-to-child transmission (MTCT) of HBV remains an important source of chronic infection in endemic areas. The risk of developing chronic HBV infection is inversely proportional to age at the time of exposure, and the risk is as high as 90 per cent for those exposed at birth1,2. The combination of postnatal passive (i.e. vaccination) and active [i.e. hepatitis B immunoglobulin (HBIG)] immunization significantly reduces neonatal transmission rates. However, appropriate immunoprophylaxis fails to protect approximately 10 per cent of infants born to mothers at highest risk for transmission from chronic infection3,4.
There is a growing body of literature to support use of antiviral therapy late in pregnancy to reduce risk of breakthrough neonatal infections among women at increased risk for neonatal transmission, such as those with hepatitis Be antigen (HBeAg)-positive disease who have high levels of HBV DNA in serum5. Maternal serum HBV DNA titre appears to be directly related to risk for MTCT6,7. While an exact threshold of risk is difficult to quantify, there appears to be general consensus that the risk is significantly higher if maternal HBV DNA exceeds 200,000 IU/ml (>106 copies/ml) at the time of delivery8,9. It is currently recommended that hepatitis B surface antigen (HBsAg)-positive mothers have serum HBV DNA quantification toward the end of the second trimester (wk 26-28 gestation), to allow for the initiation of third-trimester therapy if indicated after a thorough discussion of risks and benefits. Antiviral therapy can then be stopped post-partum with careful monitoring for disease activity in patients who do not otherwise meet criteria for chronic HBV treatment.
There are limited prospective randomized controlled trials (RCTs) examining the efficacy of antiviral therapy in pregnancy for the prevention of transmission. A recent meta-analysis of 26 studies concluded that antiviral therapy (in addition to passive-active immunization) reduced the risk of HBV transmission (risk ratio 0.3, 95% confidence interval 0.2-0.5) with no increased risk of adverse outcomes; however, the quality of available data was poor overall, with a dearth of prospective data or RCTs5. Three antiviral agents have been studied and are considered acceptable for use in pregnancy5,9,10,11,12,13,14. Much of the clinical safety data for HBV antivirals pertain to tenofovir and lamivudine because these agents are also used in HIV, and since 1989, the Antiretroviral Pregnancy Registry (APR)15 has been evaluating the teratogenic effects of HIV agents and confirmed that birth defect rates from lamivudine or tenofovir exposure were comparable to those seen in the general population16. Telbivudine is also considered safe and effective, though based on a relatively limited number of short term trials, and less rigorous safety data5,11,13. Entecavir and adefovir, also used to treat chronic HBV, have inadequate safety data in pregnancy and should not be used in this setting. In practice, tenofovir is generally preferred for use for MTCT prevention in late pregnancy given rapid viral load reduction and efficacy, tolerability, and minimal risk of viral resistance if required for longer term use12,14,17,18.
Much of the clinical data regarding third-trimester tenofovir use are derived from cohort and observational studies. Chen et al12 assessed the efficacy of tenofovir in reducing MTCT in a non-randomized prospective study of 118 e-antigen positive Taiwanese women with high viral load (HBV DNA >107.5 IU/ml) who received either standard of care or tenofovir in the third trimester until one month post-partum. They concluded that tenofovir was efficacious overall: only one of 65 treated infants was HBsAg positive by six months, compared to six of 65 untreated (1.54 vs. 10.71%, P=0.0481). However, on long term follow up, a second child was found to be HBV-infected, which ultimately resulted in similar rates of MTCT as compared to the untreated group at the end of the study12.
To further address the question of third-trimester antiviral safety and efficacy, Pan et al14 have contributed the first RCT comparing tenofovir to standard care for preventing MTCT among mothers with high viral load. In this trial, 200 HBeAg-positive mothers with HBV DNA level >200,000 IU/ml were randomly assigned to receive standard care without antiviral therapy or to receive a 300 mg oral dose of tenofovir [tenofovir disoproxil fumarate (TDF)] from 30 to 32 wk gestation to post-partum week four and were followed to postpartum wk 28. All infants received immunoprophylaxis: 200 IU of HBIG intramuscular and 10 μg of HBV vaccine within 12 h of birth, followed by two subsequent vaccine doses, as per the World Health Organization guidelines19. At delivery, 68 per cent of mothers in the tenofovir-treated group had an HBV DNA level <200,000 IU/ml as compared to two per cent of the control group. At post-partum wk 28, the rate of MTCT was significantly lower in the tenofovir-treated group as compared to controls for both the intention-to-treat analysis (5 vs. 18%, P=0.007) and the per-protocol analysis (0 vs. 7%, P=0.01). There were no neonatal infections among treated mothers. In addition, there was no significant difference in the maternal and infant safety profiles including congenital disabilities. A higher proportion of women had elevation of the alanine aminotransferase (ALT) levels after discontinuation of TDF than untreated women (45 vs. 30%, P=0.03). The authors concluded that tenofovir safely reduced the rates of MTCT, supporting a key role of third-trimester antiviral therapy in a larger randomized trial of high-risk women.
This quality trial provides further clinical data regarding the safety and efficacy of tenofovir in pregnancy; however, additional research is needed to elucidate the optimal timing of antiviral initiation. In this study12, 68 per cent of mothers who started treatment between 30 and 32 wk achieved HBV DNA <200,000 IU/ml by delivery, suggesting that nearly one-third of women continued to have levels above the HBV DNA threshold defined as conferring high risk for transmission. Some have suggested that antiviral prophylaxis should start earlier to maximize the likelihood of suppressed HBV DNA at the time of delivery, accounting for potentially early births13,14. However, the risks of earlier foetal exposure have not been assessed against the risk of prophylaxis failure.
The majority of our evidence regarding safety of antivirals and in particular, tenofovir during pregnancy is derived from the APR data, documenting safety of antivirals in the setting of HIV infection, when used throughout pregnancy15. These registry data suggest that the rate of congenital disabilities among infants with exposure to tenofovir (2.4%) was similar to the rate in the general population16. The limitations of the APR include underreporting and lack of long-term follow up of infants. There have been more reports of lower bone mineral content in newborns exposed to tenofovir throughout pregnancy among HIV-infected women20. In theory, use of antiviral therapy in the third trimester should ameliorate risks of teratogenicity. However, a study showed that mean bone mineral content was 12 per cent lower in the third-trimester tenofovir-exposed infants as compared to controls21. The long-term clinical significance of this finding is unclear and requires further study. Tenofovir alafenamide (TAF) is a prodrug of TDF that has similar antiviral efficacy at lower doses and results in lower tenofovir concentrations in blood, with improved renal and bone safety parameters. However, TAF is not yet approved for the use in pregnancy. Despite favourable safety profiles for select agents, for the purposes of reducing MTCT, antiviral therapy should be initiated later in pregnancy, thus minimizing potential risk associated with foetal exposure.
Transmission of HBV through breastfeeding is considered low risk in infants who receive immunoprophylaxis, and breastfeeding for HBV-positive mothers is recommended. On the other hand, oral nucleos(t)ide analogues have been shown to be excreted in breast milk, and there are relatively limited data regarding the effect of these antivirals on infants. In the study by Pan et al14, women were instructed not to breastfeed for the first four weeks post-partum until drug discontinuation. Accumulating evidence from HIV-positive mothers suggests that infant exposure to tenofovir in breast milk is minimal and not associated with adverse effects15,22. However, there are relatively limited data on the safety of tenofovir use during breastfeeding among HBV-infected women from existing trials. These issues highlight the importance of a clear discussion with patients of the risks and benefits of initiating antiviral therapy during pregnancy and continuation thereafter.
In the management of pregnant women with chronic HBV infection, the risks and benefits for both the mother and infant should be considered independently when deciding on antiviral therapy. The majority of HBV-infected women of childbearing age have mild disease, and the treatment is often not indicated given low levels of inflammation and/or liver fibrosis. While identification of patients at high risk for transmitting chronic infection to their infant is an important goal, it is also critical to identify and treat HBV among women of childbearing age at risk for liver-related complications who would benefit from longer term antiviral therapy, regardless of their pregnancy status. On the other hand, for women who become pregnant while taking HBV antivirals, there are risks to stopping therapy for those who have clear indications for treatment but desire to minimize foetal exposure to HBV medications. Unless continued for the clinical benefit of the mother, antiviral therapy can be withdrawn immediately in the post-partum period. Upon discontinuation at any point during or after pregnancy, women should be monitored carefully for HBV disease flares. In a prior report, ALT flares following antiviral withdrawal were common23. In the study by Pan et al14, elevation in ALT was observed more often in the treatment group and 89 per cent had viral rebound after stopping therapy, although there were no clinically significant disease flares or cases or genotypic resistance. It is not clear whether women themselves benefit from short-term third-trimester therapy, and further data supporting the optimal timing and potential risk of antiviral discontinuation are needed.
The burden of chronic HBV varies significantly worldwide. The greatest relevance of this topic is clearly in highly endemic countries such as China, where a >8 per cent prevalence of chronic infection is found, and 5-10 per cent of chronic infections are estimated to occur through MTCT24. The prevalence of chronic HBV infection in India ranges from 2 to 4 per cent, defined as low-intermediate endemicity24,25,26. The available data suggest that <1.5 per cent of pregnant women in India are HBV-infected, yet estimates vary widely, and the burden of chronic infections secondary to MTCT is unknown and may be underestimated27,28.
In summary, the management of HBV infection in pregnancy needs to be individualized and the risks of treatment need to be considered individually for both the mother and foetus, as well as the benefits to the neonate; in addition, the risk of discontinuation of therapy after delivery needs to be weighed for the mother versus the potential risks of neonatal exposure to antiviral therapy via breast milk. Pan et al14 have contributed the first RCT of tenofovir, a preferred first-line agent, for use in the third trimester to reduce MTCT risk without compromising maternal or foetal safety. However, additional information is needed to determine the optimal threshold for antiviral therapy, timing of initiation and withdrawal, benefit to the mother and longer term safety for neonates.
This editorial is published on the occasion of World Hepatitis Day - July 28, 2017