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Tenofovir alafenamide fumarate therapy for the prevention of hepatitis B vertical transmission in highly viremic mothers with chronic hepatitis B
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TAF in Pregnancy Helps Prevent Maternal Transmission of HBV to Infants
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Tenofovir alafenamide (TAF) taken during the second and third trimester helped prevent mother-to-child transmission of HBV in a 71-woman, 73-infant nationwide observational analysis in China [1]. A similar 116-woman/117-infant study in China will be presented later at AASLD The Liver Meeting [2]. Both studies involved women with chronic HBV infection and an HBV load above 200,000 IU/mL.
Researchers who conducted the 71-woman study [1] noted that randomized controlled trials found lower perinatal transmission of HBV in women with high HBV loads taking the anti-HBV agents lamivudine, telbivudine, and tenofovir disoproxil fumarate (TDF). To assess the impact of TAF in preventing HBV transmission, a China/US team planned this multicenter, single-arm national cohort study [1], which was published online a few months before AASLD The Liver Meeting [3].
The investigators retrospectively enrolled women positive for HBeAg (indicating active HBV infection) with HBV DNA above 200,000 IU/mL. All women took TAF to prevent perinatal HBV transmission between December 4, 2018 and May 18, 2020. At birth infants received hepatitis B immunoglobulin, and they got the HBV vaccination at birth, 1 month, and 6 months.
The 71 women enrolled averaged 30.3 years in age when they started TAF in the second or third trimester. They took this anti-HBV nucleotide for an average 12.8 weeks until delivery. Neither women nor infants had severe adverse effects, and infants had no congenital defects or malformations. Growth measures in infants did not vary much from national standards for physical development. Eleven of 71 women (15.5%) had postpartum alanine aminotransferase (ALT) flares, with an average ALT peak of 140.2 U/mL.
Adherence to daily TAF before delivery stood at 77.5%. Sixty-one of 71 women (86%) reached an HBV DNA load below 200,000 IU/mL by delivery. HBV DNA dwindled by an average 3.69 log10 IU/mL from starting TAF to delivery, when HBV load averaged 4.09 log10 IU/mL (about 12,000 IU/mL).
After completing the immunoprophylaxis described above by age 24 to 28 weeks, all infants tested negative for HBsAg (indicating current HBV infection) and had undetectable HBV DNA (below 100 IU/mL). Two thirds of infants breastfed, and this did not affect chances of HBV acquisition.
The researchers concluded that TAF prophylaxis during pregnancy raises no safety concerns for mothers or infants and contributes to prevention of mother-to-child HBV transmission. They called for prospective studies with longer follow-up to confirm their results. Meanwhile, the investigators believe their study "suggests that TAF should be considered as one of the first-line treatments for preventing mother to child transmission [of HBV] in this special population" [3].
References
1. Ding Y, Cao L, Zhu L, et al. Tenofovir alafenamide fumarate therapy for the prevention of hepatitis B vertical transmission in highly viremic mothers with chronic hepatitis B. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 20.
2. Zeng QL, Yu Z, Wang FS. Tenofovir alafenamide to prevent perinatal hepatitis B transmission in mothers with high viral load: a multicenter, prospective, observational study. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 160.
3. Ding Y, Cao L, Zhu L, et al. Efficacy and safety of tenofovir alafenamide fumarate for preventing mother-to-child transmission of hepatitis B virus: a national cohort study. Aliment Pharmacol Ther. 2020;52:1377-1386. doi: 10.1111/apt.16043.
https://onlinelibrary.wiley.com/doi/abs/10.1111/apt.16043
Efficacy and safety of tenofovir alafenamide fumarate for preventing mother-to-child transmission of hepatitis B virus: a national cohort study
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Summary
Background
Data on tenofovir alafenamide fumarate (TAF) for preventing mother-to-child transmission of hepatitis B virus (HBV) are lacking.
Aims
To investigate the efficacy and safety of TAF therapy for preventing hepatitis B mother-to-child transmission.
Methods
Mothers with chronic HBV infection, positive for hepatitis B e-antigen and with HBV DNA >200 000 IU/mL received TAF for preventing mother-to-child transmission were enrolled retrospectively from multiple centres with data collection on mother-infant dyads up to postpartum week 24-28. Primary measurements were the mother-to-child transmission rate and infants' malformation rate. Secondary assessments included maternal HBV DNA reduction at delivery, and maternal or infant adverse events during follow up.
Results
Among 71 mothers enrolled, the mean (±SD) age was 30.3 (±2.2) years. TAF was initiated during the second or third trimester and continued to delivery with a mean (±SD) duration of 12.8 (±4.0) weeks. At delivery, 85.9% (61/71) of the mothers achieved HBV DNA <200 000 IU/L. Seventy-three infants (two sets of twins) were born from mothers treated with TAF and none had congenital defects or malformations. All infants received HBV immunoglobulin and vaccine at birth with additional HBV vaccinations at one and six months. At age 24-28 weeks, all infants had negative hepatitis B surface antigen and undetectable levels of HBV DNA (<100 IU/mL). Body weight, height, and head circumferences were comparable to national standards for physical development. No severe adverse effects were reported in either mothers or infants.
Conclusions
TAF for highly viraemic mothers effectively prevented mother-to-child transmission of hepatitis B. There were no safety concerns for either mothers or infants with 24-28 weeks of follow up.
3 RESULTS
3.1 Study patients and treatment duration
Among 91 mother infant dyads screened, 71 mothers were eligible and enrolled in the study. The majority of non-eligible mothers were those who were lost to follow up due to relocation to another city or had missing HBV virological test results (Figure 1). The mean (±SD) maternal age was 30.3 (±2.2) years with median [interquartile range, IQR] gestational age of 27 [24, 30] weeks at the time of initiating TAF treatment. Prior to initiating TAF therapy, hepatitis D virus specific total antibodies were tested in 52% (37/71) of mothers, and the results were all negative. All mothers were treated with oral TAF (brand name-Vemlidy, Gilead Science, Inc) at the dose of 25 mg daily (patients were instructed to take it every 24 hours at any time of each day) for a mean (±SD) duration of 12.8 (±4.0) weeks before the delivery. All mothers were compliant with the treatment during pregnancy except for 22.5% (16/71) of mothers that had skipped one or more doses of TAF medication (self-reported) ranging from 1 to 7 days during pregnancy. No mothers received amniocentesis during pregnancy.20 Immediately after delivery, 78.9% (56/71) mothers discontinued the treatment. Between delivery and the last study follow up at postpartum week 24-28, 14.1% (10/71) mothers discontinued TAF treatment, with a median (range) of 30 (1-92) days on TAF after delivery. At postpartum week 24-28, a total of 93.0 % (66/71) mothers had discontinued treatment, while 7.0% (5/71) continued taking TAF through to the end of the study period. All pregnancies were singleton except for two sets of twins. Thus, the total number of live-births from 71 mothers was 73 infants. The characteristics of mothers at baseline and infants at birth are presented in Table 1.
3.2 Assessments of vertical transmission and congenital defects
The primary efficacy assessment in the study was the mother to child transmission rates among infants who were born to highly viraemic mothers treated with TAF during pregnancy. The median (range) time between the infant's birth and their receiving of the hepatitis B immune globulin (100 IU) along with the first dose of recombinant HBV vaccine (10 µg) intramuscularly was 5.5 (2-24) hours. Forty-five percent (33/73) and 40% (29/72) of infants received the immunoprophylaxis within 2 hours and within 3-6 hours at birth respectively. The HBV vaccine was supplied by the following manufacturers in China: Dalian Hissen Bio-Pharmaceutical Co., Ltd, Dalian; Shenzhen Kangtai Biological Products Co., Ltd, Shenzhen; Hualan Biological Engineering Co., Ltd, Henan; and Beijing Tiantan Biological Products Co., Ltd, Beijing. All infants completed the additional two vaccinations at their age of 1 and 6 months. Among 73 infants, 52 were tested at birth with venous blood specimens for HBV marker and HBV DNA; all were HBsAg negative with non-detectable levels of serum HBV DNA (<100 IU/mL). At the age of 24-28 weeks, all infants were tested HBsAg negative. In addition, all infants had serum HBV DNA tested at the age of 24-28 weeks, which were all below the level of detection (<100 IU/mL). Thus, there was no mother to child transmission of HBV in our study patients. In addition, all infants (73/73) developed HBsAb levels above 10 IU/mL at the age of 24-28 weeks, which was considered a completed response to HBV vaccination. There were no congenital malformations nor defects reported in the entire cohort at birth and at the age of 24-28 weeks.
3.3 TAF effects on maternal virological parameters
Regarding viral suppression during pregnancy, the adherence rate to TAF therapy before delivery was 77.5% (taking TAF daily). At delivery, 85.9% (61/71) of mothers achieved serum HBV DNA levels below 200 000 IU/mL. The reduction in the mean (±SD) level of maternal serum HBV DNA from the time points of initiating treatment to delivery was 3.7 (±1.1) log10 IU/mL during the TAF treatment, resulting in a mean (±SD) level of HBV DNA of 4.1 (±1.1) log10 IU/mL at the time of delivery. Additional analysis on viral suppression showed that 14.1% (10/71) of mothers achieved HBV DNA <100 IU/mL at delivery. Among 66 mothers who discontinued TAF therapy after delivery, 92.4% (61/66) of them had detectable HBV DNA levels (>100 IU/mL) at postpartum week 24-28. Although the mean level of maternal HBsAg decreased significantly at delivery after TAF treatment when compared to that of baseline, the mean maternal HBsAg level at postpartum week 24-28 was similar to that at baseline. Data on TAF treatment effects and maternal HBV DNA viral breakthrough during pregnancy or postpartum were presented on Table 2. One mother (1.4%) had HBeAg loss during TAF therapy prior to the delivery, but none of them had HBsAg seroconversion during the study.
3.4 Maternal adverse events and complications
During the treatment of TAF, all mothers tolerated TAF therapy well and there was no treatment discontinuation among mothers due to adverse events. Ten itemised adverse events or complications were presented in the current study based on medical record reviewed. The adverse events with frequency >2% were vomiting, upset stomach, nausea, gestational diabetes mellitus, and postpartum ALT flares (Table 3). All symptoms were reported on the severity of grades I-II and there were no maternal severe adverse events observed in the entire cohort. In terms of laboratory abnormalities, none of the mothers had ALT flares on TAF treatment during pregnancy (n = 0/71). However, 15.5% (11/71) of them had postpartum ALT flares, with a mean (±SD) ALT peak level of 140.2 (±81.3) U/mL, without the consequences of elevation of total bilirubin levels, decrease in albumin levels, or coagulopathy. The ALT flares may be due to TAF therapy cessation, as 81.8% (9/11) had stopped taking TAF after delivery. Data on ALT flares and changes in HBV DNA levels in mothers who discontinued the treatment vs those who continued on TAF is presented on Table 4. In the two patients (n = 2/11) who were on postpartum TAF treatment and developed ALT flares, their peak ALT levels during flares were 149 and 159 U/mL. No hepatic decompensation was observed among patients with ALT flares on TAF therapy.
Although there was no decline on the mean estimated glomerular filtration rates (calculated with CKD-EPI equations) during TAF treatment before delivery, a statistically significant increase in the mean (±SD) serum creatinine level from baseline (52.9 ± 9.5 µmol/L) to delivery (56.3 ± 9.7 µmol/L, P = 0.04) was observed (Table 2). However, there were no significant changes on the mean (±SD) serum phosphorous levels between the baseline (3.6 ± 0.6 mg/dL) and at the time of delivery (3.7 ± 0.5 mg/dL, P = 0.58).
3.5 Infant's adverse events, breastfeeding and physical growth
There were no negative events for any foetus in the cohort. The mean (±SD) gestational age of infants was 38.2 (±2.9) weeks, and the rate of caesarean section was 35.6% (26/73). Although there was no severe adverse events observed in infants (Table 2), common adverse events (>5%) were diarrhoea, vomiting, constipation and eczema. Breastfeeding status was assessed for all infants: 57.5% (42/73) fed with breastmilk only, 34.2% (25/73) fed with formula feeding and 8.2% (6/73) fed their infants with both. None of them were infected with HBV at the age of 24-28 weeks.
The physical development of infants with foetal exposure to TAF were within the normal range,21 except that the mean (±SD) head circumference among girls at birth was significantly smaller than that of the national standard (33.2 ± 1.02 cm vs 33.7 ± 1.3 cm; P = 0.001) However, the aforementioned parameter had exceeded the national standards when girls grew up to the age of 24-28 weeks (43.4 ± 2.6 cm vs 42.6 ± 1.2 cm; P = 0.01). All other physical growth parameters for infants with foetal exposure to TAF were comparable to or exceeded the national children's growth reference standard at birth or the age of 24-28 weeks.21 Stratified by sex gender, data comparisons between physical growth parameters of infants with foetal exposure to TAF and the national standards for infants' growth are presented in Table 5.
4 DISCUSSION
In this study, we report data from a retrospective national cohort on TAF therapy for the prevention of mother to child transmission under real-world conditions. To the best of our knowledge, this is the first study involving a significant number of infants with foetal exposure to TAF for the evaluation of efficacy and safety of TAF in highly viraemic chronic hepatitis B mothers. We observed that TAF initiated at the second or early third trimester appears to be safe for both mothers and infants during the 24-28 week follow-up period. There was no congenital defects nor malformations found among infants after the exposure. With the use of maternal TAF treatment during pregnancy in combination with standard infant HBV immunoprophylaxis, there was a 100% success rate in preventing mother to child transmission in the current study. In addition, the treatment was well tolerated and there were no major safety concerns for both mothers and infants during a short-term follow-up. Our investigation provides very important evidence to support the use of TAF during pregnancy in highly viraemic mothers as an alternative option to TDF therapy.
The effects of TAF for HBV DNA reduction were similar to TDF in pivotal trials.22, 23 In the current study with TAF therapy for a mean (±SD) of 12.8 (±4.0) weeks, maternal mean (±SD) level of HBV DNA was suppressed to 4.1 ± 1.1 log10 IU/mL with 85.9% (61/71) of patients achieved the target level of below 200 000 IU/mL at delivery. When compared with the real world study of TDF by Wang et al,24 93.7% of mothers in their study achieved the HBV DNA level of <200 000 IU/mL at delivery. These differences could be due to the higher maternal HBV DNA levels prior to initiating TAF treatment in our study. However, the HBV DNA reduction rate before delivery in our study was similar to that of mothers treated with TDF in the randomized control trial performed by Jourdain et al (88% achieved the target level).25
None of the mothers had changes in their HBsAg and HBeAg status during the study period except one who had HBeAg loss, which is expected because of the short TAF therapy duration and the relatively low efficacy of oral antiviral agents for HBV seroconversion, especially in the genotype B and C dominant Asian patient population.6 Because of the maternal HBeAg positive status at delivery, 77% of infants had positive HBeAg at birth but became negative at the age of week 24-28. The transient HBeAg positivity could be from the passage of maternal HBeAg protein through the placentas.7
Postpartum ALT flares have been a major concern for both clinicians and patients when taking antiviral therapy during pregnancy and most patients may discontinue the treatment during postpartum period due to lack of medical indication for long term therapy. Current international guidelines recommend that the cessation of antiviral treatment in these patients should be planned for anytime between delivery and postpartum week 12.5, 11 However, the optimal timing has not been determined yet. For the convenience of breast-milk feeding and concern over uncertainty of TAF concentration in the breast-milk, most patients in the current study stopped the therapy after delivery. ALT flares occurred in 15.5% (11/71) of patients without hepatic decompensation. Because of the heterogeneity in the definition of "ALT flare" among studies, it is difficult to compare the frequency of ALT flares in our study with that of other studies. The current postpartum ALT flare rate after the cessation of TAF appears to be high. Further studies with randomized designs on stopping TAF may provide better data on understanding the post-treatment ALT flares in mothers after delivery. Our study observed that TAF could be discontinued right after delivery. The increase of creatinine levels when mothers received TAF therapy in our study suggests that the monitoring of renal functions are needed during pregnancy. Although data for breast-milk feeding were limited in our study, there was no transmission of HBV observed in the cohort. Further studies should be conducted for the safety assessment of breast-milk feeding when mothers are taking TAF.
Recent advances have been made in establishing the safety and efficacy of TDF therapy during pregnancy in high viraemic mothers for preventing mother to child transmission of HBV.10, 19, 24 This is a critical step for achieving the World Health Organization (WHO) goal for global elimination of HBV infection in 2030 since there is no cure therapy available at the present time. In addition, the prevention of HBV infection in children is the most effective way by far for the reduction of global burden of hepatocellular carcinoma from HBV. Data from our study on the role of TAF therapy in HBV prevention would potentially provide opportunities for future studies on this option to fill the knowledge gap and provide evidence for the enhancement of perinatal care in chronic hepatitis B mothers.
Several limitations exist in our study. Obviously, the study inherited the shortcomings of the retrospective study design, which includes possible missing data on potential confounding factors with unknown effects on the study outcomes. Another major limitation is the lack of a control group in our study because finding matching cases without antiviral therapy in highly viraemic mothers is not feasible under the current standard of care. The follow up duration in the current study was within 28 weeks. Therefore, the long term consequences of foetal exposure to TAF have not been investigated yet. In addition, adverse events with a frequency of less than 5% might not be detected in the current sample size. Despite these limitations, our findings are important in understanding the role of TAF on the prevention of mother to child transmission for CHB mothers with high viral load. The safety data in the current study collectively contribute to the database of antiviral therapy during pregnancy. Considering the recent goals set by the World Health Organization for the elimination of HBV, our findings provide timely evidence for selecting TAF therapy as a viable option for the target population to achieve these goals. In addition, the study data was generated from multiple centres in a real-world setting with clear clinical implications, which may help enhance this study's generalizability.
In conclusion, our study indicated that TAF treatment at the second or early third trimester for pregnant women with chronic hepatitis B and high levels of viraemia displayed a 85.9% rate of viral suppression to the target level (serum HBV DNA <200 000 IU/mL) at delivery and a 100% success rate in preventing mother to child transmission when their infants received standard immunoprophylaxis. TAF therapy also has favourable safety profiles for both mothers and infants when used during the second or third trimester during pregnancy for chronic hepatitis B mothers. In the short term outcome assessments, there were no safety concerns on maternal use of and foetal exposure to TAF, except that maternal renal function should be monitored. Further studies with prospective design and long-term follow-up are needed to verify the findings above. Our preliminary data suggests that TAF should be considered as one of the first-line treatments for preventing mother to child transmission in this special population.
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