"HBV unIversal vs Point-Of-Care-based Antiviral treatMent to Prevent Mother-to-child Transmission"

I) Methodology and Study Design

The study combines two components:

I. Core Research Study Study Design Two-Arm Parallel, Cluster-Randomized Trial Design, Open-Label, Non-Inferiority Trial 1:1 Allocation Ratio 1:1 Arm 1: Intervention Group (Selective Strategy) HBsAg-positive women → Tested for HBcrAg RDT → TDF treatment if HBcrAg positive.

Arm 2: Control Group (Universal Strategy) HBsAg-positive women → Immediate TDF treatment

Clusters Randomization unit: Primary Health Centers (PHCs) or rural hospitals Total clusters: 80 (40 per group, 16 clusters per country)

Participants Total participants: 3200 HBsAg-positive women 1600 women per group → 640 women per country → 40 per cluster

Key eligibility criteria for clusters include:

• Rural or semi-rural location.
• No involvement in similar strategies
• No routine HBV DNA or HBeAg testing.
• Enough antenatal care visits to reach the target of 40 HBsAg-positive women in one year
• At least two nurses or midwives.
• HBV vaccination program in place
• Motivation to participate.

II. The Social Science component:

The social sciences component of the study will be conducted in only 2 countries (Cambodia and Ivory Coast) and includes three key sub-studies:

• The socio-economic and behavioral study aims to assess i) the acceptability of the two strategies by the healthcare workers involved in implementing the trial in the study sites and by the pregnant women who will participate in the trial and benefit from HBV PMTCT interventions, ii) the impacts of the strategies on health literacy, HBV knowledge, perceived health, treatment adherence and retention into care, iii) women experience related to HBV status disclosure and perceptions on HBV partner and children screening
• The health economic evaluation will analyze the strategies' costs, benefits, and cost-effectiveness, considering health and cost outcomes over the study period and the long term.
• The health policy study will evaluate the feasibility and sustainability of the strategies at the institutional level and explore political, institutional, and social factors that influence integrating the study results into national health policies.

A mixed-methods approach will be used, including qualitative interviews and quantitative questionnaires among pregnant women and healthcare workers.

Additionally, a qualitative assessment of the two strategies' acceptability, alongside a health policy analysis, will be conducted in Togo to enrich the study's contextual understanding. This initiative will also enhance the partner team's social science research capacity through targeted training and skill development in qualitative research for students and early-career researchers.

II) Intervention:

Medication: Tenofovir Disoproxil Fumarate (TDF); Administration Route: Oral Dosage: 300 mg/day or 300 mg every 2 days (if creatinine clearance is 30-50 ml/min)

Preventive treatment:

• Initiated during inclusion visit (if eligible for treatment in group 1, and for all in group 2)
• Continued until the 6-8 weeks postpartum visit Post-partum assessment and treatment At 3-month postpartum, all HBsAg-positive women will undergo a liver disease assessment at the closest district or provincial hospital. This assessment will include HBV DNA, HBeAg, HBcrAg-RDT, ALT/AST, platelet count, and liver ultrasound. Criteria for resuming treatment will follow the 2024 WHO guidelines. In case of TDF resumption, the treatment will be funded by the trial for 6 months, and the woman will be followed at a district or provincial hospital

III) Statistical methods

Core research study. The investigators predict that with the universal strategy, the proportion of women meeting the primary endpoint would be 78%. They chose a non-inferiority margin of 10% when comparing the HBcrAg-RDT strategy to the universal strategy. This indicates that a 68% success rate would be accepted for the same primary endpoint under the worst-case HBcrAg-RDT strategy.

They plan to recruit 40 HBsAg-positive women in each PHC. With a coefficient of variation between clusters of 0.143, derived from the assumptions, the trial requires 40 clusters per group, totaling 80 clusters of 40 HBsAg-positive women each, for 90% power at two-sided 5% (2.5% one-sided) significance to show non-inferiority within a margin of 10%.

Social Science quantitative data:

The sample size for the social science data is based on the proportion of women with good knowledge of hepatitis B, 90% power, two-sided 5% significance, and 20% loss to follow-up at the 9-month postpartum visit. Assuming 23% and 29% of women having good knowledge of hepatitis B at inclusion and the 9-month postpartum visit, respectively, overall for both strategies, with a correlation coefficient before-after of 0.15, 32 clusters (16 per country) of 40 women each (totaling 1280 participants) will be needed to show significant differences in the proportion of women with good knowledge of hepatitis B between inclusion and the 9-month postpartum visit (overall, considering both strategies together).

Inclusion criteria

• ≥18 years old, or ≥ the legal age of majority as defined by each country, on the day of inclusion.
• Pregnancy.
• Intention to attend antenatal care visits in the Primary Health Center or the Rural Hospital
• Living in an area covered by the Primary Health Center or the Rural Hospital on the start date of the trial
• Positive HBsAg identified during the screening phase of the study
• Free, informed, and written consent, signed by the person and the investigator at the latest on the day of inclusion and before any examination carried out as part of the study.

Exclusion criteria

• HIV co-infection.
• HBV treatment ongoing on the day of inclusion.
• Having at least one of the following criteria indicatives of the third trimester of pregnancy:

• Gestational Age-Based Exclusion:

The reported gestational age is ≥28 weeks, based on the last menstrual period (LMP) if known.

• Ultrasound-Based Exclusion:

Fetal biometry (e.g., head circumference, femur length) on ultrasound suggests a gestational age of ≥28 weeks.

• Fundal Height-Based Exclusion:

Symphysis-fundal height (SFH) measurement of ≥ 28 cm which corresponds to approximately 28 weeks of gestation.

• Severe gravid disease at inclusion, which poses a life-threatening risk to the mother and/or child
• Any concomitant medical condition that, according to the clinical site investigator, would contraindicate participation in the study.
• Concurrent participation in any other study (unless approved in writing by the Global Principal Investigators).