Bringing to an end mother-to-child transmission of hepatitis B: A role for quantitative hepatitis B surface antigen?

Abstract

Chronic hepatitis B infection remains prevalent in many low- and middle-income countries. Mother-to-child transmission (MTCT) has been the major route of hepatitis B virus (HBV) transmission in many parts of the world and an important factor in maintaining the reservoir of the infection in some regions, particularly in China and South-East Asia.1 In the absence of HBV vaccination, a large proportion of viremic mothers, particularly those who are hepatitis B e antigen (HBeAg) positive, transmit infection to their infants perinatally. Transmission early in life is also associated with a very high risk of lifelong chronic infection.2 It is therefore important that the most effective interventions to prevent MTCT or horizontal transmission of HBV are identified and utilized.3 The pivotal strategy for the prevention and control of hepatitis B recommended by the World Health Organization (WHO) is to deliver the first dose of hepatitis B vaccine as soon as possible after birth, preferably within 24 hours, followed by at least two more doses. Unfortunately, birth dose administration is not universal because out-of-hospital births are common in countries with high HBV endemicity, and Global Alliance for Vaccines and Immunization funding is not available for monovalent hepatitis B birth dose vaccine in many countries. Hepatitis B immune globulin (HBIG) prophylaxis, in conjunction with HBV vaccination, may be of additional benefit for infants whose mothers are HBeAg positive or have high levels of viremia, but HBIG administration is not feasible in many endemic regions. Despite both HBV vaccination and/or HBIG prophylaxis, a proportion of infants born to hepatitis B surface antigen (HBsAg)-positive mothers acquire hepatitis B. This risk of transmission is related to levels of maternal viremia: Very high maternal HBV-DNA concentrations (typically observed in HBeAg-positive women) of greater than 107 IU/mL confer a 10% or more risk of transmission.4 Failure of prophylaxis resulting in childhood infection is one of the key barriers to preventing morbidity from end-stage liver disease and hepatocellular carcinoma. A growing body of data suggest that maternal treatment with nucleoside analogs in the third trimester of pregnancy, in addition to HBV vaccine, and given the very limited access to HBIG for the infant, may reduce MTCT of HBV as well as offset the effect of imperfect adherence to infant vaccination schedules in many settings, as well as the absence of the initial birth dose of vaccine in highly viremic mothers. Wen et al. provide evidence that quantitative HBsAg testing may provide a simpler test to facilitate the prevention of perinatal transmission of hepatitis B infection.5 The 2015 WHO guidelines on prevention, care, and treatment of persons with chronic hepatitis B infection examined the evidence: Overall, the results suggested that maternal treatment with either lamivudine or telbivudine or tenofovir during the third trimester of pregnancy could be clinically effective and cost-effective in reducing the vertical transmission of hepatitis B infection when compared to no treatment or placebo. However, there was no formal recommendation for routine use of antiviral therapy to prevent MTCT because of the limited evidence base, limited evaluation of the potential harms of antiviral use in pregnancy, and the very limited access to HBV-DNA assays.6 Several important controlled clinical trials have since reported reduced MTCT in infants born to telbivudine-, lamivudine-, or tenofovir-treated HBsAg-positive mothers. For example, Pan et al. reported that tenofovir disoproxil fumarate reduced perinatal transmission of hepatitis B in highly viremic mothers. In a multicenter, prospectively randomized, and controlled study, 200 HBeAg-positive pregnant women with HBV DNA concentrations greater than 200,000 IU/mL were randomized to receive no antiviral therapy or tenofovir 300 mg daily from gestational weeks 30-32 to 4 weeks postpartum. All infants received prophylaxis with HBIG and hepatitis B vaccine. At postpartum week 28, the MTCT rate was significantly lower in infants born to tenofovir-treated mothers, when compared to those from nontreated mothers, both by per-protocol analysis (0% vs. 7%) and intention-to-treat analysis (5% vs. 18%).7 Other recent studies have confirmed the benefit of antiviral therapy in the last trimester of gestation with either telbivudine or lamivudine (vs. no treatment) in significantly reducing MTCT, without alterations in gestational age, infant height, weight, Apgar scores, or birth defect rates between infants from treated or untreated groups.8 The American Association for the Study of Liver Diseases has recently recommended that antiviral therapy be administered to HBsAg-positive pregnant mothers in the third trimester whose levels of HBV DNA exceed 200,000 IU/mL.9 Several countries have adopted an ad-hoc policy of treating highly viremic pregnant mothers with lamivudine, telbivudine, or tenofovir, especially in Asia. Such treatment is often for a limited period for the purpose of reducing HBV-DNA concentrations and hence the risk of infection to the baby. Implementation of a policy of antiviral treatment to prevent MTCT would require a means to identify those pregnant women at higher risk of MTCT. In order to ascertain higher levels of circulating HBV, testing for either HBeAg, or ideally, quantitation of HBV-DNA concentrations in serum is required. However, access to HBV-DNA measurement remains very limited and unaffordable in most resource-limited and high-prevalence regions (US$100-$400 per test), although there may be cost reductions in the near future. Quantitative HBsAg testing may provide a practical, more accessible alternative. In their study, Wen et al., from Taiwan, have examined the accuracy and predictive power of testing maternal HBsAg concentrations to identify highly viremic pregnant mothers and risk of MTCT that could avoid the high costs and complexity associated with HBV-DNA measurement. All 162 infants with HBeAg-positive mothers and 90.9% of infants with HBeAg-negative mothers received HBV vaccine and HBIG administration. Chronic HBV infection was confirmed in 19 infants after 594 deliveries in 568 mothers. The infection rate was 3.6% (19 of 526) in infants born to HBsAg-positive mothers, but 11.7% (19 of 162) to HBeAg-positive mothers. In this study, quantitative HBsAg was measured by a chemiluminescent microparticle immunoassay and sample dilution to obtain a reading within the calibration curve range. The values were log transformed. Higher HBsAg concentrations were associated with a greater risk of MTCT. Infants with maternal HBV-DNA viral load above 6-7 log log10 IU/mL or infants with a maternal HBsAg level above 4.0-4.5 log10 IU/mL had a substantial risk of perinatal infection. A strong positive quantitative correlation was found between maternal HBsAg and maternal HBV-DNA concentrations, particularly in the HBeAg-positive mothers. The optimal cutoff of maternal HBsAg concentrations to predict maternal HBV DNA higher than 6, 7, and 8 log10 IU/mL, respectively, was 3.63, 4.3, and 4.32 log10 IU/mL (a 4 log10 IU/mL concentration of HBsAg equates to an HBsAg concentration of 10,000 IU/mL). The estimated rates of infection at maternal HBsAg levels of 4, 4.5, and 5 log10 IU/mL (10,000, rounded to 30,000 and 100,000 IU/mL) were 2.4%, 8.6%, and 26% respectively. The investigators conclude that the optimal cutoff of maternal HBsAg level to predict perinatal infection was 4.1 log10 IU/mL (rounded to 12,500) IU/mL with a sensitivity of 100% and a specificity of 71%. These data suggest a potentially useful clinical application for quantitative HBsAg testing as a substitute for HBV-DNA measurement to identify pregnant mothers whose infants might benefit from third trimester antiviral therapy. Other studies have also suggested a correlation between high maternal viremia and quantitative HBsAg in HBeAg-positive Asian women.10 A cost-effectiveness analysis of testing suggested that HBsAg quantitation is highly sensitive for predicting maternal viremia, with a significant cost difference of $20,000 versus HBV-DNA testing to prevent one transmitted infection.11 Overall, these findings support a potentially simplified alternative strategy of a quantitative HBsAg test to ascertain high levels of viremia, rather than a test for HBeAg or HBV DNA. However, in Taiwan, as the investigators point out, 29% of mothers would be unnecessarily treated with antiviral therapy to prevent transmission. Commercial quantitative HBsAg assays are becoming available.12 Importantly, identifying women at risk of transmitting HBV will still require screening of all pregnant women for HBsAg. Moreover, the role of quantitative testing in sub-Saharan Africa versus Asia is less certain. There has been very limited evaluation of quantitative HBsAg testing in sub-Saharan Africa, for HBV genotypes that are not common in China and the Pacific rim countries, or in human immunodeficiency virus (HIV)/HBV-coinfected mothers, including those already receiving antiviral therapy. Although the overall risk of MTCT is lower in sub-Saharan Africa (where HBeAg-negative disease predominates), the use of antiviral therapy to reduce MTCT may nevertheless be important in this setting given that the adoption of birth dose vaccination is particularly low. Nucleoside analog treatment should be based on clinical trial evidence of safety and efficacy and projected safety in pregnancy.9, 13 The costs of generic treatments are low relative to current diagnostic costs—for example generic tenofovir is widely available from around $50 per year, procured through HIV antiretroviral treatment programs. Information on the safety of breastfeeding with tenofovir alafenamide (TAF) in the postpartum period is not yet available, but TAF is associated with less renal and bone toxicity. The timely introduction of safe and effective measures to reduce MTCT worldwide would be welcome to finally end this pernicious, but potentially preventable, route of transmission. If, annually, only 1% of infants born in sub-Saharan Africa are perinatally infected with HBV, this incidence exceeds incident pediatric HIV infection (190,000). The data from Wen et al. suggest that HBsAg quantitation, at least in regions of Asia and perhaps elsewhere, could predict the risk of MTCT infection and determine appropriate intervention to reduce the risk. Geoffrey Dusheiko, M.B. B.Ch., F.C.P.(S.A.), F.R.C.P.1 Philippa Easterbrook, M.D.2 1University College London Medical School and Kings College Hospital London, United Kingdom 2Global Hepatitis Program HIV Department World Health Organization Geneva, Switzerland