Department of Obstetrics and Gynaecology, Faculty of Medical Sciences, College of Medicine, University of Nigeria Nsukka/University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu State, Enugu, Nigeria.
Effective Care Research Unit, Department of Obstetrics and Gynaecology, Faculty of Medicine, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, PMB 5001, Nnewi, Nigeria.
Cochrane Database Syst Rev. 2023 Jun 12;6(6):CD013653. doi: 10.1002/14651858.CD013653.pub2.
Hepatitis B virus (HBV)-human Immunodeficiency virus (HIV) co-infection promotes an aggressive disease course of HBV infection. In the only available non-Cochrane systematic review on antiviral therapy during pregnancy for prevention of mother-to-child transmission of HBV, none of the women studied had HBV-HIV co-infection but were either HBV- or HIV-seropositive. Treatment of HBV alone may develop HIV-strains that are resistant to non-nucleoside reverse transcriptase inhibitors. Accordingly, co-treatment of the HIV infection is recommended.
To evaluate the benefits and harms of tenofovir-based antiviral combination regimens versus placebo, tenofovir alone, or non-tenofovir-based antiviral regimen either alone or in combination with HBV for the prevention of mother-to-child transmission of HBV in HIV-positive pregnant women co-infected with HBV.
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, LILACS (Bireme), Science Citation Index Expanded (Web of Science), and Conference Proceedings Citation Index-Science (Web of Science) on 30 January 2023. We manually searched the reference lists of included trials, searched on-line trial registries, and contacted experts in the field and pharmaceutical companies for any further potential trials.
We aimed to include randomised clinical trials comparing tenofovir-based antiviral combination regimens (anti-HIV regimen with lopinavir-ritonavir therapy, or any other antiviral therapy, and two drugs with activity against HBV, specifically, tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), plus lamivudine or emtricitabine) with placebo alone, or tenofovir alone, or non-tenofovir-based antiviral regimen (zidovudine, lamivudine, telbivudine, emtricitabine, entecavir, lopinavir-ritonavir, or any other antiviral therapy) either alone or in combination with at least two other antivirals.
We used standard methodological procedures expected by Cochrane. Primary outcomes included all-cause infant mortality, proportion of infants with serious adverse events, proportion of infants with HBV mother-to-child transmission, all-cause maternal mortality, and proportion of mothers with serious adverse events. Secondary outcomes included proportion of infants with adverse events not considered serious, proportion of mothers with detectable HBV DNA (deoxyribonucleic acid) (before delivery), maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion (before delivery) and maternal adverse events not considered serious. We used RevMan Web to carry out analyses and presented results, where feasible, using a random-effects model and risk ratios (RR) with 95% confidence intervals (CIs). We performed sensitivity analysis. We assessed risk of bias using predefined domains, assessed the certainty of the evidence using GRADE, controlled risk of random errors with Trial Sequential Analysis, and presented outcome results in a summary of findings table.
Five completed trials were included, of which four trials contributed data to one or more of the outcomes. They included a total of 533 participants randomised to tenofovir-based antiviral combination regimens (196 participants) versus control (337 participants). The control groups received non-tenofovir-based antiviral regimens either as zidovudine alone (three trials) or as a combination of zidovudine, lamivudine and lopinavir-ritonavir (five trials). None of the trials used placebo or tenofovir alone. All trials were at unclear risk of bias. Four trials used intention-to-treat analyses. In the remaining trial, two participants in the intervention group and two in the control group were lost to follow-up. However, the outcomes of these four participants were not described. Tenofovir-based antiviral combination regimen versus control We are very uncertain about the effect of a tenofovir-based antiviral combination regimen versus control on all-cause infant mortality (RR 2.24, 95% CI 0.72 to 6.96; participants = 132; trials = 1; very low-certainty evidence); proportion of infants with serious adverse events (RR 1.76, 95% CI 1.27 to 2.43; participants = 132; trials = 1; very low-certainty evidence), and proportion of mothers with serious adverse events (RR 0.90, 95% CI 0.62 to 1.32; participants = 262; trials = 2; very low-certainty evidence). No trial reported data on the proportion of infants with HBV mother-to-child transmission and all-cause maternal mortality. We are also very uncertain about the effect of tenofovir-based antiviral combination regimens versus control on the proportion of infants with adverse events not considered serious (RR 0.94, 95% CI 0.06 to 13.68; participants = 31; trials = 1; very low-certainty evidence), and proportion of mothers with detectable HBV DNA (before delivery) (RR 0.66, 95% CI 0.42 to 1.02; participants = 169; trials = 2; very low-certainty evidence). No trial reported data on maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion (before delivery) and maternal adverse events not considered serious. All trials received support from industry.
AUTHORS' CONCLUSIONS: We do not know what the effects of tenofovir-based antiviral combination regimens are on all-cause infant mortality, proportion of infants with serious adverse events and proportion of mothers with serious adverse events, proportion of infants with adverse events not considered serious, and proportion of mothers with detectable HBV DNA before delivery because the certainty of evidence was very low. Only one or two trials, with insufficient power, contributed data for analyses. We lack randomised clinical trials at low risk of systematic and random errors, and fully reporting all-cause infant mortality, serious adverse events and reporting on clinical and laboratory outcomes, such as infants with HBV mother-to-child transmission, all-cause maternal mortality, maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion before delivery and maternal adverse events not considered serious.
乙型肝炎病毒 (HBV)-人类免疫缺陷病毒 (HIV) 合并感染可促进 HBV 感染的侵袭性疾病过程。在唯一一项关于预防乙型肝炎母婴传播的妊娠期抗病毒治疗的可用非 Cochrane 系统评价中，没有研究对象同时感染 HBV 和 HIV，但均为 HBV 或 HIV 血清阳性。单独治疗 HBV 可能会产生对非核苷类逆转录酶抑制剂耐药的 HIV 株。因此，建议联合治疗 HIV 感染。
评估替诺福韦为基础的抗病毒联合治疗方案与安慰剂、替诺福韦单药或非替诺福韦为基础的抗病毒联合方案（单独或联合使用拉米夫定和恩曲他滨）在预防 HIV 阳性合并感染 HBV 的孕妇母婴传播中的益处和危害。
我们于 2023 年 1 月 30 日在 Cochrane 肝胆病组对照试验注册库、Cochrane 对照试验中心注册库、MEDLINE Ovid、Embase Ovid、LILACS（Bireme）、科学引文索引扩展版（Web of Science）和会议论文集引文索引科学版（Web of Science）进行了检索。我们手动检索了纳入试验的参考文献列表，检索了在线试验注册库，并联系了该领域的专家和制药公司以获取任何其他潜在的试验。
我们旨在纳入比较替诺福韦为基础的抗病毒联合治疗方案（含洛匹那韦利托那韦治疗或任何其他抗病毒治疗的抗 HIV 方案，以及两种具有抗 HBV 活性的药物，即替诺福韦阿法酰胺（TAF）或替诺福韦二吡呋酯（TDF）加拉米夫定或恩曲他滨）与安慰剂、替诺福韦单药或非替诺福韦为基础的抗病毒联合方案（齐多夫定、拉米夫定、替比夫定、恩曲他滨、恩替卡韦、洛匹那韦利托那韦或任何其他抗病毒治疗）单独或联合使用至少两种其他抗病毒药物的随机临床试验。
我们使用了 Cochrane 预期的标准方法学程序。主要结局包括全因婴儿死亡率、严重不良事件发生率、婴儿母婴传播率、全因产妇死亡率和严重不良事件发生率。次要结局包括无严重不良事件的婴儿不良事件发生率、无严重不良事件的母亲 HBV DNA（脱氧核糖核酸）可检测率（分娩前）、产妇乙型肝炎 e 抗原（HBeAg）至 HBe 抗体血清转换（分娩前）和无严重不良事件的母亲不良事件发生率。我们使用 RevMan Web 进行分析，并在可行的情况下使用随机效应模型和风险比（RR）和 95%置信区间（CI）呈现结果。我们进行了敏感性分析。我们使用预定的领域评估偏倚风险，使用 GRADE 评估证据的确定性，使用试验序贯分析控制随机错误风险，并在汇总结果表中呈现结局结果。
纳入了五项已完成的试验，其中四项试验的数据贡献给了一个或多个结局。它们共纳入了 533 名参与者，分为替诺福韦为基础的抗病毒联合治疗组（196 名参与者）与对照组（337 名参与者）。对照组接受非替诺福韦为基础的抗病毒联合方案（三项试验为齐多夫定单药治疗，五项试验为齐多夫定、拉米夫定和洛匹那韦利托那韦联合治疗）。没有试验使用安慰剂或替诺福韦单药治疗。所有试验的偏倚风险均为不确定。四项试验采用意向治疗分析。在其余一项试验中，干预组和对照组各有两名参与者失访。然而，这四名参与者的结局没有被描述。替诺福韦为基础的抗病毒联合治疗组与对照组我们非常不确定替诺福韦为基础的抗病毒联合治疗组与对照组在全因婴儿死亡率（RR 2.24，95%CI 0.72 至 6.96；参与者=132；试验=1；极低确定性证据）、严重不良事件发生率（RR 1.76，95%CI 1.27 至 2.43；参与者=132；试验=1；极低确定性证据）和严重不良事件发生率（RR 0.90，95%CI 0.62 至 1.32；参与者=262；试验=2；极低确定性证据）方面的效果。没有试验报告婴儿母婴传播率和全因产妇死亡率的数据。我们也非常不确定替诺福韦为基础的抗病毒联合治疗组与对照组在无严重不良事件的婴儿不良事件发生率（RR 0.94，95%CI 0.06 至 13.68；参与者=31；试验=1；极低确定性证据）和无严重不良事件的母亲 HBV DNA 可检测率（分娩前）（RR 0.66，95%CI 0.42 至 1.02；参与者=169；试验=2；极低确定性证据）方面的效果。没有试验报告产妇乙型肝炎 e 抗原（HBeAg）至 HBe 抗体血清转换（分娩前）和无严重不良事件的母亲不良事件发生率的数据。所有试验均得到了行业的支持。
由于证据的确定性非常低，我们不知道替诺福韦为基础的抗病毒联合治疗方案在全因婴儿死亡率、严重不良事件发生率和严重不良事件发生率、无严重不良事件的婴儿不良事件发生率以及无严重不良事件的母亲 HBV DNA 可检测率方面的效果如何。只有一到两项试验，且样本量不足，提供了分析所需的数据。我们缺乏低偏倚风险和充分报告全因婴儿死亡率、严重不良事件和报告临床和实验室结局（如母婴传播、全因产妇死亡率、产妇乙型肝炎 e 抗原（HBeAg）至 HBe 抗体血清转换和无严重不良事件的母亲不良事件）的随机对照临床试验。
