The COMBAT HBV Feasibility Trial

The overall study design is a randomized, double-blind, placebo-controlled trial among two groups of mother-infant dyads: women who receive TDF vs placebo in late pregnancy and the postpartum period (beginning at 28-32 weeks' gestation and continuing through 4 weeks' postpartum). While official World Health Organization (WHO) recommendations are to continue TDF at least through delivery, a range from delivery through 12 weeks' postpartum is possible; the investigators will continue therapy through 4 weeks' postpartum in this study. This feasibility trial will evaluate the acceptability, safety and preliminary effectiveness of a TDF-for-all approach to prevent MTCT of HBV in low-resource settings. HBsAg-positive pregnant women will be enrolled at 28-32 weeks' gestation, and will present for regular medication checks, with a study closeout visit at 24 weeks' postpartum. Study activities at monthly medication checks will include medication refills, assessment of adherence (via pill counts and verbal surveys), and evaluation for side effects. All infants will receive a birth-dose of HBV vaccine within 24 hours of life. MTCT of HBV will be defined as the proportion of infants with positive HBsAg testing at 6 months. This pilot study will provide preliminary data for sample size calculations, including safety and effectiveness data, to prepare for larger RCTs to determine the effectiveness of a tenofovir-for-all approach, as well as the added benefit of tenofovir over birth-dose vaccination.

• Tenofovir Disoproxil Fumarate 300 MG (Drug), also known as Viread: Pregnant women in the experimental arm will receive TDF daily beginning in the 3rd trimester of pregnancy and continuing through 1 month postpartum.
• Hepatitis B monovalent vaccine (Biological), also known as Hepatitis B birth-dose vaccine, Engerix-B: All infants born to women in the study will receive a birth-dose hepatitis B vaccine.
• Placebo (Drug): Pregnant women in the placebo arm will receive a placebo pill daily beginning in the 3rd trimester of pregnancy and continuing through 1 month postpartum.

Primary outcomes

• Safety (Pregnant Women): Number of Pregnant Women With Adverse Effects Related to Study Medications [Up to study close-out visit, or up to 12 months]: Safety of TDF prophylaxis in pregnant women, defined as a composite of adverse events (# mild adverse events \[AEs\], # moderate-to-severe AEs), presence of side effects and alanine aminotransferase elevations ≥ 5x upper limit of normal
• Safety (Infants): Number of Infants with Adverse Effects Related to Study Medications [At delivery]: Safety of maternal TDF for infants, defined as a composite of: Birth weight (grams), mid-upper arm circumference (centimeters), gestational age at delivery (weeks and days), delivery mode (vaginal vs C-section), APGAR scores (0-10), # of adverse events
• Feasibility (Recruitment): Number of Eligible Participants Who Were Enrolled in the Study [Up to study close-out visit, or up to 12 months]: Recruitment is indicative of the number of pregnant women who are screened versus those actually enrolled in the study.
• Feasibility (Refusal): Number of Eligible Participants Who Refused to Enroll in the Study [Up to study close-out visit, or up to 12 months]: Refusal will be defined as the number of individuals who refuse enrollment upon initial recruitment.
• Feasibility (Withdrawal): Number of Enrolled Participants Who Withdraw from the Study [Up to study close-out visit, or up to 12 months]: Withdrawal is indicative of the number of enrolled participants who choose not to continue study activities after having been enrolled.
• Feasibility (Retention): Number of Enrolled Participants Who Remain in the Study Through 6 Months Postpartum [Up to study close-out visit, or up to 12 months]: Retention is defined as the number of participants who remain in the study through the 6-month postpartum visit.
• Feasibility (Maintenance): Proportion of Study Visits Completed Per Participant [Up to study close-out visit (12 months)]: Adherence to study visits and procedures, defined as proportion of the actual number of visits attended divided by the expected study visits (8) and multiplied by 100.
• Acceptability (Lab Testing): Number of Mothers With Lab Testing Acceptability Scores >80% [Upon study close-out visit, or up to 12 months]: Number of mothers who report the process of undergoing lab draws as "acceptable" in the exit survey. Range 0-100%, with 0% being unacceptable and 100% being acceptable.
• Acceptability (Medication): Number of Mothers With Medication Acceptability Scores >80% [Upon study close-out visit, or up to 12 months]: Number of mothers who report the process of taking the study medication as "acceptable" in the exit survey. Range 0-100%, with 0% being unacceptable and 100% being acceptable.
• Preliminary Effectiveness: Number of Infants With HBV Positivity by Rapid Diagnostic Testing at 6 Months of Life to Indicate Mother-to-Child Transmission of HBV [Measured at 6 months after birth]: Mother-to-child transmission of HBV is defined as HBsAg positivity in the infant at 6 months of life.

Secondary outcomes

• Sensitivity of the Hepatitis B Core-Related Antigen Test [Measured at Enrollment]: Sensitivity will be defined as the number of true positive tests divided by the sum of the true positives and false negatives.
• Specificity of the Hepatitis B Core-Related Antigen Test [Measured at Enrollment]: Specificity will be defined as the number of true negative tests divided by the sum of the true negatives and the false positives.

Sex: All

Inclusion Criteria:

* Pregnant women ≥18 years of age who present for routine prenatal care between 28-32 weeks' gestation and who test HBV-positive by point-of-care hepatitis B surface antigen test. Women must intend to seek maternity and postpartum care exclusively at one of the Kinshasa-based study maternity centers.
* Infants born to enrolled women will be included in the study

Exclusion Criteria:

* Individuals with abnormal creatinine by point-of-care testing
* Any woman who plans to move outside of Kinshasa Province during the study period.
* Any HIV-positive individual, determined by routine point-of-care screening at antenatal care visits

• Peyton Thompson, MD, MSCR, Principal investigator, University of North Carolina, Chapel Hill