Antiviral Therapy for Hepatitis B Transmission Prevention

(REVERT-B Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Jodie Dionne, MD, MSPH

Age: < 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: University of Alabama at Birmingham

Must not be taking: Tenofovir

Disqualifiers: HIV, Liver cirrhosis, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests antiviral drugs to prevent hepatitis B transmission from mothers to babies. It focuses on high-risk pregnant women and their newborns in Africa. The drugs lower virus levels in mothers and protect babies until they are vaccinated. One of the drugs, Tenofovir disoproxil fumarate (TDF), has been studied for its ability to prevent the spread of hepatitis B from mothers to their babies.

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.

What data supports the effectiveness of the drug Lamivudine in preventing hepatitis B transmission?

Research shows that Lamivudine can reduce the transmission of hepatitis B from mother to child during pregnancy. It is also effective in initially controlling the virus in many patients, although resistance can develop over time. ^{1 2 3 4 5}

Is the antiviral therapy for hepatitis B safe for humans?

The antiviral treatments, including Tenofovir Disoproxil Fumarate and Lamivudine, have been shown to be safe and well-tolerated in humans for treating chronic hepatitis B, with Tenofovir recognized as a first-line treatment option. ^{4 6 7 8 9}

What makes the drug Lamivudine Oral Solution and Tenofovir Disoproxil Fumarate unique for preventing hepatitis B transmission?

This drug combination is unique because it uses two potent antiviral agents, lamivudine and tenofovir, which have different resistance profiles, potentially reducing the risk of drug resistance and improving treatment effectiveness for hepatitis B. Additionally, tenofovir is recognized for its once-daily administration, making it convenient for patients. ^{2 7 10 11 12}

Research Team

Jodie Dionne, MD, MSPH

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Lamivudine Oral Solution (Nucleoside Reverse Transcriptase Inhibitor)
• Tenofovir Disoproxil Fumarate (Nucleotide Reverse Transcriptase Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Kierstin Kennedy

University of Alabama at Birmingham

Chief Medical Officer since 2022

MD

S. Dawn Bulgarella

University of Alabama at Birmingham

Chief Executive Officer since 2023

BSc in Commerce and Business Administration from the University of Alabama, MS in Health Administration from the University of Alabama at Birmingham

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

Collaborator

Trials

2,103

Recruited

2,760,000+

Dr. Diana W. Bianchi

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

Chief Executive Officer since 2016

MD from Stanford University

Dr. Alison Cernich

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

Chief Medical Officer since 2020

PhD in Clinical Psychology from University of Maryland

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Chronic hepatitis B: preventing, detecting, and managing viral resistance. [2008]

3. China pubmed.ncbi.nlm.nih.gov

[RtL164V, a mutation possibly associated with lamivudine resistant HBV]. [2013]

4. India pubmed.ncbi.nlm.nih.gov

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

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Current antiviral therapy for chronic hepatitis B. [2018]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical efficacy of lamivudine in the treatment of chronic hepatitis B]. [2013]

7. Spain pubmed.ncbi.nlm.nih.gov

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

8. United States pubmed.ncbi.nlm.nih.gov

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. [2022]

9. Iran pubmed.ncbi.nlm.nih.gov

Tenofovir in the treatment of hepatitis B virus infection after liver transplantation, a single center large population study. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

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

12. Argentina pubmed.ncbi.nlm.nih.gov

[Therapy of chronic hepatitis B]. [2009]