Antiviral Therapy for Hepatitis B Transmission Prevention

(REVERT-B Trial)

Overseen By Jamie White

Age: < 65

Sex: Female

Trial Phase: Phase 3

Sponsor: University of Alabama at Birmingham

Must not be taking: Tenofovir

Disqualifiers: HIV, Liver cirrhosis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to prevent hepatitis B transmission from mothers to newborns during delivery. Researchers are testing the antiviral medication Tenofovir Disoproxil Fumarate for pregnant women and Lamivudine Oral Solution for newborns to evaluate their effectiveness and safety. The trial seeks pregnant women with active hepatitis B who are at risk of passing it to their babies. Participants should plan to deliver at the study facility and be able to provide informed consent. Their involvement will aid in finding effective strategies to prevent hepatitis B in newborns. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking prevention methods.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking tenofovir.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Tenofovir Disoproxil Fumarate (TDF) is generally safe for pregnant women to use in preventing hepatitis B transmission to their babies. Studies indicate that TDF significantly reduces the risk of virus transmission to newborns and is well-tolerated by mothers. Most women did not experience major side effects, though some reported mild issues like an upset stomach or dizziness.

For the babies, the study examines Lamivudine, which is already commonly used for other conditions. This suggests it might be safe for newborns, but specific information on its use for preventing hepatitis B in newborns remains less clear. As this trial is in a late stage, there is a good chance that both treatments are well-tolerated. Always discuss potential risks with the study team or your doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for preventing hepatitis B transmission because they offer new approaches for both mothers and newborns. Unlike standard treatments, Tenofovir Disoproxil Fumarate (TDF) is being tested for early initiation during pregnancy, potentially improving outcomes by starting treatment as soon as 14 weeks. For newborns, Lamivudine is being explored as a post-exposure prophylaxis, which is not a typical standard for infants exposed to hepatitis B at birth. This combination of early intervention for mothers and direct treatment for infants could significantly reduce the risk of hepatitis B transmission.

What evidence suggests that this trial's treatments could be effective for preventing hepatitis B transmission?

Studies have shown that Tenofovir Disoproxil Fumarate (TDF), which participants in this trial may receive, greatly reduces the chance of mothers passing hepatitis B to their newborns. Research indicates that starting TDF treatment as early as the 16th week of pregnancy can effectively prevent the virus from being transmitted to the baby at birth. This treatment, combined with infant vaccinations, can even eliminate the need for additional medical treatments like HBIG (Hepatitis B Immunoglobulin). The evidence strongly supports TDF as a safe and effective way to lower the risk of hepatitis B transmission in high-risk pregnancies. Meanwhile, another arm of this trial evaluates the use of Lamivudine for newborn infants exposed to HBV at birth. ^{1 3 6 7 8}

Who Is on the Research Team?

Jodie Dionne, MD, MSPH

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for pregnant women over 16 years old in Africa, between 14-32 weeks of pregnancy, who have active hepatitis B with a high risk of passing it to their baby. They must plan to deliver at the study facility and be able to consent. Women can't join if they are HIV positive, have very high liver enzymes or serum creatinine levels, are already on tenofovir medication, or have known allergies to the study drugs.

Inclusion Criteria

Prenatal clinic patient

I am 16 years old or older.

Plan to receive follow up care and deliver at study facility

Exclusion Criteria

You are currently pregnant and your baby has a known abnormality.

I am currently hospitalized due to my illness.

You are allergic to or cannot tolerate the study medication called tenofovir.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Pregnant women receive Tenofovir (TDF) starting from the 2nd or 3rd trimester until delivery; newborns receive Lamivudine (3TC) or placebo for 6 months

6 months

Regular prenatal visits and postnatal visits for infants

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of vertical transmission and adherence

6-9 months after delivery

Follow-up visits at 6-9 months post-delivery

Extension

Optional long-term follow-up for additional safety and efficacy assessments

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Lamivudine Oral Solution
• Tenofovir Disoproxil Fumarate

Trial Overview The REVERT-B study is testing whether antiviral medications Tenofovir Disoproxil Fumarate and Lamivudine Oral Solution can prevent mothers from passing hepatitis B to their newborns during delivery. The effectiveness, safety, how well people tolerate the meds, and adherence will be monitored.

How Is the Trial Designed?

Group I: Pregnant Women - Tenofovir Experimental Treatment 1 Intervention

Women will be randomized to early initiation (enrollment at 14-28 weeks pregnant) vs standard initiation (at 28 weeks pregnant) of tenofovir disoproxil fumarate (TDF) 300 mg daily oral medication until delivery.

Group II: Newborn Infants - Lamivudine Placebo Group 1 Intervention

Infants exposed to HBV at birth will be randomized to receive oral lamivudine post-exposure prophylaxis or matching placebo. Medication will be administered twice daily for 6 months.

Lamivudine Oral Solution is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Epivir for:

• HIV infection
• Chronic hepatitis B

Approved in United States as Epivir for:

• HIV infection
• Chronic hepatitis B

Approved in Canada as Epivir for:

• HIV infection
• Chronic hepatitis B

Approved in Japan as Epivir for:

• HIV infection
• Chronic hepatitis B

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

Lamivudine, an oral nucleoside analogue, shows promise in preventing and treating recurrent hepatitis B infection after liver transplantation, which is a significant concern for patient survival.

If successful, lamivudine maintenance therapy could reduce or eliminate the need for expensive and limited hepatitis B immune globulin (HBIg) treatment, with further studies planned to confirm its efficacy in a multicenter trial supported by the National Institutes of Health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter studies of Lamivudine for the treatment and prevention of hepatitis B after liver transplantation. Perrillo, R.[2023]

The introduction of oral antivirals for Chronic Hepatitis B treatment has expanded therapy options, allowing for the treatment of patients with advanced and decompensated liver disease.

A major challenge remains the emergence of drug-resistant HBV strains, highlighting the need for strategies to prevent resistance and achieve sustained viral suppression to prevent liver disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of chronic hepatitis B]. Buti, M., Esteban, R.[2009]

In a Phase 2 study involving 112 patients with chronic hepatitis B and decompensated liver disease, all three antiviral treatments (tenofovir disoproxil fumarate, emtricitabine/tenofovir, and entecavir) were well tolerated, with low rates of treatment discontinuation due to adverse events.

At 48 weeks, significant virologic improvements were observed, with 70.5% of patients on tenofovir, 87.8% on emtricitabine/tenofovir, and 72.7% on entecavir achieving HBV DNA levels below 400 copies/mL, indicating effective viral suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Liaw, YF., Sheen, IS., Lee, CM., et al.[2022]

In a 12-month study involving 40 patients co-infected with HIV and HBV, lamivudine effectively reduced HBV replication, with 96.3% of patients with high HBV replication achieving low serum HBV DNA levels by the end of treatment.

No serious adverse events were reported, indicating that lamivudine is a safe option for patients who are refractory to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Benhamou, Y., Katlama, C., Lunel, F., et al.[2019]

Chronic hepatitis B virus (HBV) infection can be treated with several licensed oral antiviral agents, including lamivudine, adefovir, entecavir, and telbivudine, as well as off-label options like tenofovir and emtricitabine, which are effective in managing the infection.

Preventing antiviral drug resistance is crucial, and using a combination of potent drugs with different resistance profiles can be the best strategy; early detection of resistance through regular monitoring of HBV DNA levels allows for timely adjustments in therapy to maintain viral suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic hepatitis B: preventing, detecting, and managing viral resistance. Keeffe, EB., Dieterich, DT., Pawlotsky, JM., et al.[2008]

Tenofovir disoproxil fumarate is a safe and well-tolerated oral medication approved for treating chronic hepatitis B, allowing for convenient once-daily dosing due to its long-lasting effects.

It has become a first-line treatment option for chronic hepatitis B, effective for both patients who are new to treatment and those who have previously received other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tenofovir disoproxil fumarate for the treatment of hepatitis B infection. Adusumilli, S.[2017]

Lamivudine is effective in rapidly suppressing HBV replication in patients with chronic hepatitis B, showing a significant HBV DNA response rate of 61% compared to 6% in the placebo group after 12 weeks.

The treatment is well tolerated with no severe drug-related adverse events reported over 104 weeks, although there is a risk of YMDD mutations leading to HBV DNA breakthrough in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy of lamivudine in the treatment of chronic hepatitis B]. Ma, H., You, H., Yin, S.[2013]

Lamivudine significantly reduces the risk of in utero hepatitis B virus (HBV) transmission, with a 10.7–23.7% lower incidence of intrauterine infection and a 12.7–33.2% lower mother-to-child transmission rate in newborns compared to no treatment or placebo.

The treatment was found to be safe, with no significant increase in adverse effects or complications during pregnancy, making it an effective option for HBV carrier mothers in late pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Shi, Z., Yang, Y., Ma, L., et al.[2022]

In a study of 21 chronic hepatitis B patients treated with a combination of Telbivudine and Tenofovir for 52 weeks, significant reductions in HBV DNA levels were observed, with 10 out of 11 patients achieving levels below 100 IU/ml by the end of the study.

The combination therapy was well tolerated with no safety concerns, and while it showed significant virologic and biochemical responses, the overall decline in HBV DNA was not greater than what is typically seen with monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Telbivudine plus tenofovir in combination therapy in patients with chronic hepatitis B infection--an Indian experience. Panda, C.[2018]

In a study of 302 liver transplant patients, tenofovir disoproxil fumarate (TDF) and lamivudine (LAM) showed comparable safety profiles, with no significant differences in kidney function or creatinine levels over a median follow-up of 42.9 months.

Both TDF and LAM were equally effective in preventing recurrent hepatitis B virus infection and acute graft rejection after liver transplantation, indicating that either medication can be a viable option for post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tenofovir in the treatment of hepatitis B virus infection after liver transplantation, a single center large population study. Ejtehadi, F., Pashaei, MR., Shamsaeefar, A., et al.[2022]

In a study of chronic hepatitis B patients undergoing lamivudine treatment, the emergence of the YMDD mutation was observed in all primary non-responders and rebounders, indicating a common resistance mechanism to the therapy.

Additionally, the rtL164V mutation was identified as a potential novel marker for lamivudine resistance, as it was present in all primary non-responders and rebounders, but not in those who responded to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[RtL164V, a mutation possibly associated with lamivudine resistant HBV]. Wang, YP., Yan, YS., Jiang, JJ.[2013]

Interferon-alpha, lamivudine, and adefovir dipivoxil are the three approved treatments for chronic hepatitis B, with all showing better rates of HBeAg loss and anti-HBe seroconversion compared to untreated patients.

Lamivudine is generally safe but has a high rate of viral resistance over time, while adefovir dipivoxil has a low resistance rate (less than 2% at 2 years) and is effective against resistant strains, making it a promising option for long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current antiviral therapy for chronic hepatitis B. Lim, YS., Suh, DJ.[2018]

Citations

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Role of tenofovir disoproxil fumarate in prevention of perinatal ... Pooled results with per-protocol analysis showed that tenofovir disoproxil fumarate (TDF) significantly decreased the perinatal transmission of hepatitis B ...

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Tenofovir and Hepatitis B Virus Transmission During ... TDF therapy at gestational week 16 combined with HBV vaccinations of infants avoided the need for HBIG and was noninferior to standard care for preventing HBV ...

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Critical Insights Into the Effectiveness and Safety of Tenofovir ... Tenofovir alafenamide versus tenofovir disoproxil fumarate for preventing vertical transmission in chronic hepatitis B mothers: a systematic review and meta- ...

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Economic evaluation of tenofovir disoproxil fumarate ... This study aimed to compare the cost-effectiveness of alternative strategies to prevent MTCT of HBV in Vietnam.

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Efficacy and safety of tenofovir in preventing mother-to ... Based on the current evidence, our study suggested that tenofovir significantly reduced the rate of vertical transmission of HBV, as well as the ...

7. academic.oup.com academic.oup.com/cid/article/79/4/953/7684177

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate ... The study conducted pair-wise and network meta-analyses to compare the efficacy and safety of maternal TAF versus TDF in preventing HBV vertical transmissi.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0301211522004316

Efficacy and safety of tenofovir disoproxil fumarate or ... Treatment of pregnant women with active CHB with TDF or LdT during their entire pregnancy was effective and safe. We found that HBV DNA levels at postpartum ...