无 HBIg 策略可防止 HBV 垂直传播——如果母亲们尽快开始 TDF

StephenW

无 HBIg 策略可防止 HBV 垂直传播——如果母亲们尽快开始 TDF

2022 年 CROI，2022 年 2 月 12-16 日和 22-24 日

马克·马斯科里尼

一项不包括乙型肝炎免疫球蛋白 (HBIg)* 的预防 HBV 垂直传播的策略在柬埔寨的一项大型研究中奏效——只要母亲在分娩前至少 4 周开始使用替诺福韦酯 (TDF) 并且新生儿及时接种了 HBV 疫苗出生后[1]。 ANRS 研究人员表示，由于该策略不依赖于 HBIg，因此可以将 HBV 传播预防分散到柬埔寨大多数孕妇接受护理的农村地区。

据 ANRS 团队称，柬埔寨孕妇的 HBV 感染率估计为 4%，而乙型肝炎表面抗原 (HBsAg) 阳性母亲所生婴儿的 HBV 感染率约为 10%，这表明存在活动性 HBV 感染。在柬埔寨和其他国家，HBV DNA 水平高于 5.3 log10 IU/mL 时，垂直 HBV 预防依赖于在出生后 24 小时内为所有婴儿接种疫苗，为出生时的婴儿接种 HBIg，以及在妊娠晚期接种母体 TDF。但柬埔寨和类似国家由于成本高昂和结构性障碍而无法轻易获得 HBIg。在低收入国家也可能很难进行 HBV DNA 检测，因此可能不得不使用 HBeAg 快速诊断测试 (RDT)。

金边健康科学大学的研究人员和其他中心的合作者计划进行这项分析，即 ANRS TA PROHM 研究，以评估无 HBIg 策略在柬埔寨预防 HBV 垂直传播的有效性。该策略包括三个部分：(1) HBsAg/HBeAg RDT 和基于丙氨酸氨基转移酶 (ALT) 的算法来筛查孕妇并决定 TDF 预防措施，(2) 对妊娠 24 周或立即治疗的合格妇女进行 TDF 治疗对于符合条件的妇女以后再看，以及 (3) 在出生后 2 小时内对所有婴儿进行疫苗接种。主要结果是按婴儿 HBIg 状态分层的 6 个月大 HBsAg 阳性婴儿的百分比以及母亲是否获得 TDF 至少 4 周。

这项单臂前瞻性试验于 2017 年 10 月至 2020 年 11 月在柬埔寨的 5 个妇产科进行。研究人员招募了在产前检查期间使用 HBeAg RDT 筛查的 HBsAg 阳性女性。如果 RDT 中 HBeAg 阳性（2017 年 10 月至 2018 年 12 月）或 RDT 中 HBeAg 阳性或阴性且 ALT 等于或高于 40 IU/L（从 2019 年 1 月起），则女性有资格获得 TDF。婴儿在出生时和第 6 周、第 10 周和第 14 周时接种了疫苗。如果可用，可以使用 HBIg，并且 5 个单位中只有 1 个使用 HBIg。

研究人员筛查了 21,251 名女性，1326 名 HBsAg 检测呈阳性，1194 名被纳入研究。在纳入的女性中，338 人（28%）符合 TDF 条件，856 人（72%）不符合条件。分娩后六个月，母亲 TDF 合格组中的 317 名婴儿和 TDF 不合格组中的 712 名婴儿接受了 HBsAg 检测。超过 96% 的婴儿在出生后 24 小时内接种了乙肝疫苗。从出生到接种疫苗的时间中位数为 15 分钟。

在所有婴儿中，6 个月大时，符合 TDF 条件的母亲所生的 1.26%（95% 置信区间 [CI] 0.34 至 3.20）的 HBsAg 检测呈阳性，而 TDF 婴儿的这一比例为 0.98%（95% CI 0.40 至 2.02） - 不合格的母亲（差异无统计学意义）。在未获得 HBIg 的婴儿中，HBsAg 阳性率分别为 1.48%（95% CI 0.40 至 3.74）和 1.06%（95% CI 0.39 至 2.30）（无统计学意义）。在未接受 HBIg 的婴儿中，如果母亲接受 TDF 超过 4 周，则没有一个 HBsAg 阳性（95% CI 0.00 至 1.61），如果他们的母亲接受 TDF 治疗，则 8.33%（95% CI 1.75 至 22.5）为阳性。不到 4 周，如果他们的母亲没有得到 TDF，则 12.50%（95% CI 0.32 至 52.65）为阳性。

在符合 TDF 条件的女性中，94.1% 的女性开始使用 TDF，78.8% 的女性每次就诊时的依从性高于 90%，89.8% 的女性服用 TDF 超过 4 周。有任何 3 级或 4 级不良事件或严重不良事件的女性比例在 TDF 合格组中为 13.9%，在 TDF 不合格组中为 5.8%。任何 3 级或 4 级不良事件或与肝细胞溶解相关的严重不良事件的比例分别为 12.4% 和 2.3%。有任何 3 级或 4 级不良事件或任何严重不良事件的婴儿比例在符合 TDF 条件的母亲中为 5.9%，在不符合 TDF 条件的母亲中为 4.2%。

研究人员得出结论，如果 TDF 在分娩前 4 周以上开始，“母亲使用 TDF 和早期接种疫苗的无 HBIg 策略可能是有效的”，以防止 HBV 的垂直传播。不使用 HBIg 并使用治疗算法（HBeAg RDT/ALT）而不是 HBV DNA 检测来选择符合 TDF 条件的女性，可以在农村地区使用这种不含 HBIg 的策略，柬埔寨的大多数孕妇都在那里接受护理。

参考
1. Segeral O、Dim B、Durier C 等人。预防 HBV 母婴传播的无 HBIg 策略：ANRS TA PROHM 研究。 2022 年 CROI，2 月 12 日至 16 日

StephenW

HBIg-Free Strategy Prevents Vertical HBV Transmission—If Mothers Start TDF Soon Enough

2022 CROI, February 12-16 and 22-24, 2022

Mark Mascolini

A strategy to prevent vertical transmission of HBV that does not include hepatitis B immune globulin (HBIg)* worked in a large Cambodian study—as long as mothers started tenofovir disoproxil (TDF) at least 4 weeks before delivery and neonates got the HBV vaccination promptly after birth [1]. Because the strategy does not depend on HBIg, ANRS researchers said, it could allow decentralization of HBV transmission prevention to rural areas where most pregnant women get care in Cambodia.

According to the ANRS team, HBV infection prevalence stands at an estimated 4% in pregnant women in Cambodia—and at 10% in infants born to mothers positive for hepatitis B surface antigen (HBsAg), which indicates active HBV infection. In Cambodia and other countries vertical HBV prevention relies on vaccinating all infants within 24 hours of birth, HBIg for infants at birth, and maternal TDF in the third trimester of pregnancy if HBV DNA lies above 5.3 log10 IU/mL. But Cambodia and similar countries cannot readily get HBIg because of high cost and structural barriers. HBV DNA assays may also be hard to come by in low-income countries, so an HBeAg rapid diagnosis test (RDT) may have to be used instead.

Researchers at the University of Health Sciences in Phnom Penh and collaborators at other centers planned this analysis, the ANRS TA PROHM study, to assess the effectiveness of an HBIg-free strategy to prevent vertical HBV transmission in Cambodia. The strategy has three parts: (1) an HBsAg/HBeAg RDT and an alanine aminotransferase (ALT)-based algorithm to screen pregnant women and decide on TDF prophylaxis, (2) TDF treatment for eligible women from 24 weeks of gestation or immediate treatment for eligible women seen later, and (3) vaccination of all infants within 2 hours of birth. The primary outcome was the percentage of HBsAg-positive infants at 6 months of age stratified by infant HBIg status and whether the mother got TDF for at least 4 weeks.

This single-arm prospective trial ran from October 2017 to November 2020 in 5 maternity units in Cambodia. Researchers enrolled HBsAg-positive women screened during antenatal care with an HBeAg RDT. Women became eligible for TDF if HBeAg-positive on the RDT (October 2017 to December 2018) or HBeAg-positive or negative on the RDT with an ALT at or above 40 IU/L (from January 2019). Infants got vaccinated at birth and weeks 6, 10, and 14. HBIg could be used if available, and only 1 of 5 units used HBIg.

Researchers screened 21,251 women, 1326 tested positive for HBsAg, and 1194 got included in the study. Of women included, 338 (28%) were eligible for TDF and 856 (72%) were not. Six months after delivery, 317 infants in the maternal TDF-eligible group and 712 in the TDF-ineligible group got tested for HBsAg. More than 96% of infants got the HBV vaccine within 24 hours of birth. A median 15 minutes passed between birth and vaccination.

At 6 months of age among all infants, 1.26% (95% confidence interval [CI] 0.34 to 3.20) born to TDF-eligible mothers tested positive for HBsAg, compared with 0.98% (95% CI 0.40 to 2.02) for infants of TDF-ineligible mothers (difference not statistically significant). Among infants who did not get HBIg, respective HBsAg-positive rates were 1.48% (95% CI 0.40 to 3.74) and 1.06% (95% CI 0.39 to 2.30) (not statistically significant). In infants who did not get HBIg, none were HBsAg-positive if their mother got TDF for more than 4 weeks (95% CI 0.00 to 1.61), 8.33% (95% CI 1.75 to 22.5) were positive if their mother got TDF for fewer than 4 weeks, and 12.50% (95% CI 0.32 to 52.65) were positive if their mother got no TDF.

Among women eligible for TDF, 94.1% started TDF, 78.8% had better than 90% adherence at every visit, and 89.8% took TDF for more than 4 weeks. Proportions of women with any grade 3 or 4 adverse event or a serious adverse event were 13.9% in the TDF-eligible group and 5.8% in the TDF-ineligible group. Respective proportions with any grade 3 or 4 adverse event or a serious adverse event related to liver cytolysis were 12.4% and 2.3%. Proportions of infants with any grade 3 or 4 adverse event or any serious adverse event were 5.9% with TDF-eligible mothers and 4.2% with TDF-ineligible mothers.

The researchers concluded that “an HBIg-free strategy with maternal use of TDF and early vaccination at birth could be effective” to prevent vertical transmission of HBV if TDF begins more than 4 weeks before delivery. Not using HBIg and using a therapeutic algorithm (HBeAg RDT/ALT) instead of an HBV DNA assay to select women eligible for TDF allows this HBIg-free strategy to be used in rural areas, where most pregnant women in Cambodia receive care.

Reference
1. Segeral O, Dim B, Durier C, et al. HBIg-free strategy to prevent HBV mother-to-child transmission: ANRS TA PROHM study. 2022 CROI, February 12-16