COMMENTARY

Perinatal Transmission of the Hepatitis B Virus

Strategies for Prevention

William F. Balistreri, MD

Disclosures

June 04, 2015

In This Article

Antiviral Treatment Among Pregnant Women

Because a high level of HBV viremia in pregnant women is a risk factor for failure of immunoprophylaxis, multiple studies have been designed to reduce the maternal viral load through administration of antiviral therapy in the third trimester, thereby limiting exposure of the neonate to HBV. Indeed, treatment of the pregnant woman with chronic hepatitis B is now being recognized as an important strategy, as data accumulate to show that selective treatment in the third trimester of pregnancy may lower risk for perinatal HBV transmission.[1,4,9,10]

Several options for therapy during pregnancy are available:lamivudine, telbivudine, and tenofovir. Administration of each of these agents has been associated with significant reductions in maternal viral loads and in the rates of perinatal transmission, with favorable safety profiles.[36] Each offers distinct advantages and disadvantages.

Lamivudine, which has been well studied, carries a pregnancy category C classification and is associated with high rates of antiviral resistance. Both telbivudine and tenofovir have a pregnancy category B designation but are less well studied in pregnancy than lamivudine.[2] Therapy with pegylated interferon, which is contraindicated in pregnancy, may be considered before pregnancy.

Lamivudine. Maternal treatment with lamivudine can significantly reduce HBV viral load and therefore reduce the risk for mother-to-child transmission.[37,38] For example, Jackson and colleagues[37] documented that after lamivudine therapy during the third trimester of pregnancy (median duration of 11 weeks), 60% of women achieved a significant (2 log) reduction in viral load before delivery. No cases of perinatal transmission occurred in the infants born to mothers who received the full course of treatment.

In another study, none of the infants born to mothers who initiated lamivudine treatment (100 mg/day) in the second or third trimester was positive for HBsAg or had detectable HBV DNA at 28 weeks of age.[39] However, initiation of lamivudine late in pregnancy resulted in the emergence of drug-resistant viral variants.[40,41]

Telbivudine. Han and colleagues[42] reported on the course of 229 HBeAg-positive mothers with high viremia who were given either telbivudine or no therapy from 20 to 32 weeks of gestation.All infants received hepatitis B vaccine and HBIg per protocol. Telbivudine administration was associated with a marked reduction in HBV DNA and HBeAg levels, with normalization of maternal ALT levels before delivery. The overall incidence of perinatal transmission (assessed at 7 months) was 0% in the telbivudine-treated group compared with 8% in the control group.

In an observational study, 86 women with chronic hepatitis B infection received telbivudine during pregnancy; none of their infants was HBsAg-positive at 6 months.[43] The treatment was considered safe during follow-up periods of up to 4 years.

Wu and colleagues[44] performed a prospective study of 450 HBeAg-positive pregnant women with elevated levels of HBV DNA; 279 women received telbivudine (600 mg /day) during weeks 24-32 of gestation, and 171 women who were unwilling to take antiviral drugs participated as controls. All newborns were vaccinated with recombinant HBV vaccine and received HBIg, according to the standard immunoprophylaxis procedure.

Levels of HBV DNA fell in the women who took telbivudine; 23% had undetectable HBV DNA at delivery, compared with none of the controls. A significantly higher proportion of women given telbivudine had undetectable levels of HBV DNA in cord blood (99%) compared with controls (62%). None of the infants whose mothers were given telbivudine tested positive for HBsAg at 6 months of age, compared with 15% of infants in the control group. No severe adverse events or complications were observed in the women or in their infants.

Similarly, Pan and colleagues[45] reported that telbivudine, administered for an average of 15 weeks at the end of pregnancy, plus passive-active immunization reduced HBV transmission rates to 4% vs 23% with immunization alone.

A meta-analysis–based review analyzed the efficacy and safety of telbivudine treatment on mother-to-child transmission of HBV from HBsAg and HBV DNA-positive mothers.[46] All newborns received the standard immunoprophylaxis schedule, consisting of simultaneous hepatitis B vaccine and HBIg postpartum. On the basis of new onset of HBsAg seropositivity in infants at 6-12 months postpartum, the control group had perinatal transmission rates ranging from 8% to 42% compared with 0% to 14% in the telbivudine treatment group.

Tenofovir disoproxil fumarate. Two studies found that the use of tenofovir prophylaxis reduced maternal HBV DNA levels and potentially perinatal transmission in highly viremic women.[47,48] There was a significant reduction in median HBV DNA levels from baseline after treatment. Tenofovir in pregnancy was well tolerated.[48] No major safety issues were associated with early tenofovir treatment in pregnant women, and no treatment-related birth defects were observed.[49,50]

Comparison Studies

HBeAg-positive mothers with serum HBV DNA level > 106 copies/mL were randomly assigned at gestation week 28 to receive telbivudine, lamivudine, or no treatment until postpartum week 4.[51] At delivery, significantly lower HBV DNA levels were measured in mothers who received lamivudine or telbivudine. None of the infants in the treated groups vs 3% in the untreated group became HBsAg-positive.The treatment was well tolerated, with no safety concerns identified.

Yu and colleagues[52] compared the efficacy and safety of telbivudine vs lamivudine in women positive for HBsAg and HBeAg.[52] The perinatal HBV transmission rate and the rate of immunization failure were 0% in both the telbivudine group and the lamivudine group, compared with 5% in the control (HBIg only) group.

Greenup and colleagues[48] conducted a multicenter, prospective, observational comparison study of antiviral safety and efficacy in pregnant women with high viral load (≥ 107 copies/mL), 96% of whom were HBeAg-positive. Lamivudine was used from 2007 to 2010, and tenofovir beginning in late 2010.[48] Viral load declined and the rate of perinatal transmission was reduced significantly to 2% and 0% in the tenofovir and lamivudine cohorts, respectively, compared with 20% in the untreated cohort.

Limitations

The strategy of antiviral treatment administered during the third trimester not only offers the advantage of reducing the risk for HBV transmission at the time of delivery but also avoids any possible teratogenic effects of antiviral therapy during the critical first trimester of fetal development.[38,42,45]

Unfortunately, this regimen has been inconsistently applied owing to the lack of a unified approach to screening and the absence of strong long-term safety data. It has been pointed out that some of the studies that reported a beneficial effect of antiviral therapy were limited by high dropout rates, small numbers, heterogeneity of the patients, methodological and clinical diversity, suboptimal immunoprophylaxis schedules, the use of historical controls for comparison, and inadequate follow-up.[7] Few studies were randomized, double-blind, controlled clinical trials; thus the evidence-based data on which to base strong recommendations for antepartum antiviral therapy are limited.[7] Moreover, the cost of antiviral therapy may be prohibitive in developing countries where HBV is endemic.[53]

Even though antiviral treatment during pregnancy of women with elevated HBV DNA levels reduces the rate of perinatal transmission, HBV DNA screening is not routinely performed in the antenatal period. For example, in one survey, only 80% of women had antenatal HBeAg testing and 22% were HBeAg-positive.[54] It has also been emphasized that HBV DNA levels are highly variable and unpredictable during pregnancy; thus, a previously healthy HBV carrier mother with a low HBV DNA level may become highly viremic during the last few weeks of pregnancy.[53] These findings suggest that routine HBeAg screening and determination of viral load in expectant HBeAg-positive mothers could identify a subset of mother/infant pairs who are at higher risk for perinatal HBV transmission.

Safety Concerns

The potential for widespread application of the strategy of third- trimester antiviral administration has also raised several concerns about the safety of this approach. These include effects on the growth and development of the infant and the potential for maternal hepatitis flares after drug discontinuation.

Zeng and colleagues[55] reported that growth and development were normal in children who were prenatally exposed to telbivudine used to treat chronic HBV infection in their mothers, indicating that telbivudine treatment during pregnancy is safe and effective. The antiretroviral registry data indicate that the use of lamivudine and tenofovir during pregnancy, even in the first trimester, did not result in an increased incidence of birth defects.[2]

Hepatitis flares may occur in the postpartum period after antiviral therapy is discontinued; therefore, the mothers should be closely monitored for 6 months after treatment is stopped.[56,57,58,59,60,61] Women who were positive for HBeAg were more likely to experience a flare than those who were negative for infection.[56,57,58]

In a study of HBsAg-positive pregnant patients, Carey and colleagues[59] reported that high HBV DNA levels during the second trimester of pregnancy were also predictive of postdelivery HBV flares.The hepatitis flaresare usually asymptomatic and resolve spontaneously.

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