Efficacy and safety of antiviral therapy for HBV in different trimesters of pregnancy: systematic review and network meta-analysis

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Abstract

Background

Several antiviral agents licenced for blocking mother-to-child transmission (MTCT) of HBV, but their relative efficacy beginning from different trimesters has scarce been evaluated. We aimed to conduct a network meta-analysis to statistically differ the efficacy and safety of each antiviral agents initiating on different timings in preventing mother-to-infant transmission of HBV.

Methods

Studies were included from PubMed, EMBASE, Web of Science, and Cochrane databases through July 1, 2019. Eligible studies recruited randomized controlled trials and nonrandomized studies reporting about infant or/and maternal efficacy and safety outcomes and were screened by two investigators independently. Extracted data were analyzed by pair-wised and network meta-analysis, respectively.

Results

3 Randomized and 32 nonrandomized studies enrolling 6738 pregnant female were included. Using network analysis, any antiviral agent interrupted HBV vertical transmission much more effectively than placebo. No agent showed significant efficacy different from others, but a strong trend toward significance was found in telbivudine and tenofovir, of which had the highest probability of being ranked the first- or second-best treatment for reducing MTCT of HBV. The treatment applied in the first and second trimester had a similar efficacy in preventing MTCT. Compared with the initiation during the third trimester, lower rate of MTCT was revealed when antiviral therapy was administrated before third trimester, (RR = 0.045, 95% CI 0.0053 to 0.20); a similar effect at delivery on suppressing maternal HBV DNA level and converting serum HBeAg were achieved if the timing of antiviral treatment started prior, but an obvious improvement of normalizing ALT flare was calculated out; no statistically differences among maternal and fetal safety outcomes were found if mothers received antiviral agents before pregnant 28 weeks.

Conclusion

This network meta-analysis recommended the earlier use of telbivudine or tenofovir, tends to be better to prevent MTCT of HBV in pregnancy with no increased adverse maternal or fetal outcomes.

Electronic supplementary material

The online version of this article (10.1007/s12072-020-10026-0) contains supplementary material, which is available to authorized users.

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Most cited references 40

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Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus.

Huey-Ling Chen, Chien-Nan Lee, Chin-Hao Chang … (2015)

The efficacy and safety of maternal tenofovir disoproxil fumarate (TDF) in reducing mother-to-infant hepatitis B virus (HBV) transmissions is not clearly understood. We conducted a prospective, multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)- and hepatitis B e antigen-positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication (control group, n = 56, HBV DNA 8.22 ± 0.39 log10 IU/mL) or TDF 300 mg daily (TDF group, n = 62, HBV DNA 8.18 ± 0.47 log10 IU/mL) from 30-32 weeks of gestation until 1 month postpartum. Primary outcome was infant HBsAg at 6 months old. At delivery, the TDF group had lower maternal HBV DNA levels (4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL, P < 0.0001). Of the 121/123 newborns, the TDF group had lower rates of HBV DNA positivity at birth (6.15% versus 31.48%, P = 0.0003) and HBsAg positivity at 6 months old (1.54% versus 10.71%, P = 0.0481). Multivariate analysis revealed that the TDF group had lower risk (odds ratio = 0.10, P = 0.0434) and amniocentesis was associated with higher risk (odds ratio 6.82, P = 0.0220) of infant HBsAg positivity. The TDF group had less incidence of maternal alanine aminotransferase (ALT) levels above two times the upper limit of normal for ≥3 months (3.23% versus 14.29%, P = 0.0455), a lesser extent of postpartum elevations of ALT (P = 0.007), and a lower rate of ALT over five times the upper limit of normal (1.64% versus 14.29%, P = 0.0135) at 2 months postpartum. Maternal creatinine and creatinine kinase levels, rates of congenital anomaly, premature birth, and growth parameters in infants were comparable in both groups. At 12 months, one TDF-group child newly developed HBsAg positivity, presumably due to postnatal infection and inefficient humoral responses to vaccines.

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Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.

M Atkins, Ling Wang, Xinmin Li … (2009)

This randomized, double-blind, placebo-controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26-30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine-treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo-treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.

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Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice

Hua Zhang, Calvin Pan, Qiumei Pang … (2014)

Little observational data exist describing telbivudine (LdT) or lamivudine (LAM) use in late pregnancy for preventing hepatitis B mother-to-child transmission (MTCT) in real-world settings. During the period of January 2009 to March 2011, we enrolled hepatitis B e antigen–positive mothers with HBV DNA >6 log10 copies/mL in China. At gestation week 28, the mothers received LdT or LAM until postpartum week 4 or no treatment (NTx). The study endpoints were the safety of LdT/LAM use and MTCT rates. Of the 700 mothers enrolled, 648 (LdT/LAM/NTx = 252/51/345) completed the 52-week study with 661 infants (LdT/LAM/NTx = 257/52/352). On treatment, viral rebound occurred in 1.6% of mothers, all resulting from medication noncompliance. There was no genotypic mutation detected. At delivery, significantly lower HBV DNA levels were noted in mothers who received LdT or LAM versus NTx. Alanine aminotransferase flares were observed in 17.1% of treated mothers versus 6.3% of untreated mothers (P < 0.001). At birth, hepatitis B surface antigen (HBsAg) was detected in 20% and 24% of newborns in the treated and NTx groups, respectively. At week 52, an intention-to-treat analysis indicated 2.2% (95% confidence [CI]: 0.6-3.8) of HBsAg+ infants from the treated group versus 7.6% (95% CI: 4.9-10.3) in the NTx group (P = 0.001) and no difference of HBsAg+ rate between infants in the LdT and LAM groups (1.9% vs. 3.7%; P = 0.758). On-treatment analysis indicated 0% of HBsAg+ infants in the treated group versus 2.84% in the NTx group (P = 0.002). There were no differences for gestational age or infants' height, weight, Apgar scores, or birth defect rates between infants from the treated and untreated groups. Conclusions: LdT and LAM use in late pregnancy for highly viremic mothers was equally effective in reducing MTCT. The treatment was well tolerated with no safety concerns identified.

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Author and article information

Contributors

Yaolong Chen: sinograde@163.com

Yuan Yang: xayanyuan@126.com

Tianyan Chen:

ORCID: http://orcid.org/0000-0003-4823-9507

chentianyan@126.com

Journal

Journal ID (nlm-ta): Hepatol Int

Journal ID (iso-abbrev): Hepatol Int

Title: Hepatology International

Publisher: Springer India (New Delhi )

ISSN (Print): 1936-0533

ISSN (Electronic): 1936-0541

Publication date (Electronic): 19 March 2020

Publication date PMC-release: 19 March 2020

Publication date Collection: March 2020

Volume: 14

Issue: 2

Pages: 180-189

Affiliations

[1 ]GRID grid.452438.c, Department of Infection Disease and Hepatopathy, , First Affiliated Hospital of Xi’an Jiaotong University, ; Xi’an, 710061 Shaanxi China

[2 ]GRID grid.452672.0, Department of Infection Disease and Hepatopathy, , Second Affiliated Hospital of Xi’an Jiaotong University, ; Xi’an, Shaanxi China

[3 ]GRID grid.32566.34, ISNI 0000 0000 8571 0482, Evidence-Based Medicine Center, Basic Medical Sciences, , Lanzhou University, ; Lanzhou, China

[4 ]WHO Collaborating Centre for Guideline Implementation and Knowledge Translation, Lanzhou, China

Author information

Tianyan Chen http://orcid.org/0000-0003-4823-9507

Article

Publisher ID: 10026

DOI: 10.1007/s12072-020-10026-0

PMC ID: 7136311

PubMed ID: 32193814

SO-VID: d8f9d1b1-f293-497e-9302-94d456b4c17b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 November 2019

Date accepted : 21 February 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100014718, Innovative Research Group Project of the National Natural Science Foundation of China;

Award ID: 81670537

Award Recipient : Jinfeng Liu

Funded by: FundRef http://dx.doi.org/10.13039/501100013317, Shanxi Provincial Key Research and Development Project;

Award ID: S2018-YF-ZDSF-0240

Award Recipient : Tianyan Chen

Funded by: National Science and Technology Projects on Major Infectious Diseases

Award ID: 2017ZX10202202-002-006

Award Recipient : Yingren Zhao

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: hepatitis b,mother-to-child transmission,pregnancy,antiviral treatment,network meta-analysis,lamivudine,telbivudine,tenofovir,efficacy,safety outcomes

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: hepatitis b, mother-to-child transmission, pregnancy, antiviral treatment, network meta-analysis, lamivudine, telbivudine, tenofovir, efficacy, safety outcomes

Efficacy and safety of antiviral therapy for HBV in different trimesters of pregnancy: systematic review and network meta-analysis

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Most cited references 40

Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus.

Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.

Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice

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