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TDF-Based Hep B Immunoglobulin-Free Strategy Stalls HBV MTCT
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EASL International Liver Congress, June 23-26, 2021
Mark Mascolini
A strategy to prevent mother-to-child transmission (MTCT) of hepatitis B virus (HBV) that relies on tenofovir disoproxil fumarate (TDF) prophylaxis-and not on hepatitis B immunoglobulin (HBIg)-proved effective in the ANRS 12345 TA-PROHM trial in Cambodia [1]. The ANRS researchers believe this simple strategy could decentralize HBV transmission prevention to the district level, where most pregnant women receive care in Cambodia. These findings may also be relevant to other countries whose MTCT HBV prophylaxis plans include HBIg.
Among pregnant Cambodian women, prevalence of hepatitis B surface antigen (HBsAg, indicating current HBV infection) stands at 4.39%. One in 10 Cambodian infants of HBsAg-positive mothers also tests positive for HBsAg, while overall HBsAg prevalence in young children stands at 0.56%. A large majority of infants born to mothers with HBV infection, 89%, currently get 3 doses of the childhood HBV vaccine. About 45% of newborns receive a vaccine dose within hours of birth.
The ANRS researchers aimed to test an HBIg-free strategy to prevent HBV MTCT in Cambodia. The strategy used an HBsAg/HBeAg RDT/ALT algorithm to screen pregnant women and decide on use of TDF prophylaxis. (HBeAg positivity suggests that a person carries and can transmit HBV.) In TDF-eligible women, the aim was to begin TDF 24 weeks after the missed period first indicating pregnancy and to continue to 6 weeks after delivery. For women first seen after the 24-week point, the study relied on a test-and-treat strategy. The strategy aimed to have newborns receive their first HBV vaccine dose within 2 hours of birth. The study's primary endpoint was the proportion of infants with active HBV infection at age 6 months by HBsAg positivity in plasma (confirmed by HBV DNA).
This nonrandomized interventional prospective study aimed to recruit 295 TDF-eligible pregnant women at least 18 years old at 5 sites in Cambodia. Infants were to receive the HBV vaccine at birth and weeks 6, 10, and 14. HBIg was not recommended but could be used if it was available.
Among 1194 HBsAg-positive pregnant women recruited, 338 (28%) were eligible for TDF and 856 were not. Among 318 women who actually began TDF prophylaxis, 317 delivered 324 infants at a study site. Among the 856 women not eligible for TDF, 746 delivered 752 infants at a study site. The study tested 317 infants of TDF-taking mothers for HBsAg, while testing 712 infants of women not taking TDF.
Median age at study entry stood at 27 years in the 338 women eligible for TDF and at 30 years in the 856 women not eligible for TDF, a significant difference (P < 0.001). A significantly higher proportion of TDF-eligible women had an initial HBV DNA load above 5.3 log10 IU/mL: 80.8% versus 11.0% (P < 0.001), and median load lay significantly higher in TDF-eligible women: 7.91 versus 2.51 log10 IU/mL (P < 0.001). A lower proportion of women eligible for TDF delivered by Caesarian section than did TDF-ineligible women (16.1% vs 22.7%). At delivery median TDF duration stood at 13.6 weeks. Among TDF-eligible women, 82.9% had an HBV DNA load below 5.3 log10 IU/mL at delivery, compared with 90.3% of TDF-ineligible women.
At birth, infants of TDF-eligible women were similar to infants of TDF-ineligible women in weight, height, head circumference, use of HBIg at birth (13.3% and 16.2%), HBV vaccine within 2 hours of birth (88.7% and 87.5%), within 24 hours of birth (97.5% and 96.2%), and within 7 days of birth (100% and 100%). Median time from birth to first vaccine dose stood at 15 minutes in both groups.
Overall proportions of infants positive for HBsAg at 6 months were 1.26% in the TDF-eligible group (95% confidence interval [CI] 0.34 to 3.20) and 0.98% (95% CI 0.40 to 2.02) in the TDF-ineligible group, not a significant difference. Among infants who did not receive HBIg, proportions positive for HBsAg at 6 months were 1.48% in the TDF-eligible group and 1.06% in the TDF-ineligible group, also a nonsignificant difference. Among infants of TDF-eligible women, HBsAg positivity measured 6.52% in those whose mothers received TDF for 4 weeks or less and at 0% in those whose mothers received TDF longer.
All 11 HBsAg-positive infants had current HBV infection confirmed by HBV DNA. Four HBsAg-positive infants were born to mothers eligible for TDF and 7 to TDF-ineligible mothers. All 4 TDF-eligible mothers whose infant tested positive for HBsAg at 6 months had an HBV load above 8 log10 IU/mL when entering the study, and all 4 mothers took TDF for less than 1 month. Maternal HBV DNA at delivery ranged from 3.3 to 6.6 log10 IU/mL in these 4 mothers. And all 4 infants received the HBV vaccine within 2 hours of birth. Among the 7 TDF-ineligible women whose infant tested positive for HBsAg at 6 months, maternal HBV DNA stood above 5.3 log10 IU/mL at study inclusion in 6 women; the remaining woman had a 4 log10 HBV DNA at inclusion. HBV DNA at delivery ranged from 4 to 8.9 log10 IU/mL in these 7 women. Six of their 7 infants got their first HBV vaccine dose within 2 hours of delivery, and the seventh infant got the first dose within 24 hours of delivery.
Grade 3 or 4 adverse events affected 10.1% of TDF-eligible women (95% CI 7.1 to 13.8), compared with 4.4% of TDF-ineligible women (95% CI 3.2 to 6.0), a significant difference. Proportions of women with at least one alanine aminotransferase more than 5 times the upper limit of normal at inclusion were 5.0% (95% CI 3.0 to 7.9) in the TDF-eligible group and 1.5% (95% CI 0.8 to 2.6) in the ineligible group, also a significant difference. Grade 3 or 4 adverse events affected 4.3% of infants of TDF-eligible mothers (95% CI 2.5 to 7.1) and 2.3% of infants of TDF-ineligible mothers (95% CI 1.4 to 3.6), not a significant difference.
The researchers stressed the high acceptability of this strategy: 94% of TDF-eligible women agreed to prophylaxis with the drug, and more than 85% of infants got their first HBV vaccine dose within 2 hours of birth, while more than 95% got their first dose within 24 hours. The ANRS team believes this HBIg-free strategy could reduce perinatal HBV transmission if mothers take TDF for more than 1 month before delivery. The investigators argue that the strategy "could have a main public health impact" by putting HBV MTCT prophylaxis at the district level, where most pregnant women receive care.
Reference
1. Segeral O, Dim B, Durier C, et al. Immunoglobulin-free alternative strategy to prevent HBV mother to child transmission in Cambodia: preliminary results of the ANRS 12345 TA PROHM study. EASL International Liver Congress, June 23-26, 2021. Abstract OS-865.
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