Doravirine for HIV in Pregnancy

Overseen By Amanda Poliseno, BS

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: University of North Carolina, Chapel Hill

Must be taking: Antiretrovirals

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Multiple gestation, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Up to 10 months

10 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to evaluate the effect of body changes in pregnancy on doravirine concentrations, to determine what dose of doravirine should be used. Study participants will remain on their normal antiretroviral medications (ARVs) while participating in this study as prescribed by their regular clinic provider. Study participants will come to the research clinic for three sampling visits throughout their time as a participant. Study participants will only take one dose of doravirine during each sampling visit, which will occur during the 2nd and 3rd trimesters, as well as after their baby is delivered. This study was designed intentionally to not give a dose of doravirine in the first trimester when there is the greatest chance for all drugs to potentially cause injury to the baby. Study participants that choose to participate in this study may be enrolled for up to 10 months depending on the length of their pregnancy and how the visits are scheduled.

Will I have to stop taking my current medications?

Participants will not have to stop taking their current antiretroviral medications, as they are required to stay on their existing treatment plan during the study. However, if you are taking certain medications that affect drug concentration, you may not be eligible to participate.

What data supports the effectiveness of the drug Doravirine for HIV treatment?

Doravirine is approved for treating HIV-1 in adults who have not had previous antiretroviral treatment, showing it is effective in this group. It has a unique resistance profile, which means it can work even when other drugs might not. ^{1 2 3 4 5}

Is Doravirine safe for use in pregnancy?

There is currently no safety data available for the use of Doravirine in pregnant women, and it is not recommended for this group due to the lack of information on its effects. ^{1 2 3 4 6}

What makes the drug Doravirine unique for treating HIV in pregnancy?

Doravirine is a newer HIV drug that is part of a class called non-nucleoside reverse transcriptase inhibitors (NNRTIs), and it has a distinct resistance profile compared to other drugs in its class. However, it is not currently recommended for pregnant women due to a lack of safety and efficacy data, making its use in pregnancy novel and under investigation. ^{1 2 3 4 6}

Research Team

Angela Kashuba, PharmD

Principal Investigator

UNC Chapel Hill

Eligibility Criteria

This trial is for HIV-positive pregnant women over 18, with stable health and on consistent antiretroviral therapy. They must have low viral loads and normal liver function. Women with severe kidney or liver issues, multiple pregnancies, certain other illnesses, or taking drugs that affect the body's drug processing are excluded.

Inclusion Criteria

I agree not to change my current HIV medication during the study.

Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the trial

I am a pregnant woman over 18 with HIV.

Exclusion Criteria

I have an active hepatitis C infection confirmed by tests.

Women with multiple gestation, active opportunistic infections, present obstetrical complications that would deem them unsuitable for study participation, or evidence of fetal anomalies in present pregnancy

I have severe kidney or liver problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of doravirine during each sampling visit in the 2nd and 3rd trimesters, and post-partum

Up to 10 months

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Doravirine

Trial Overview The study tests how pregnancy affects the levels of Doravirine (an HIV medication) in the body to determine proper dosing. Participants will take a single dose at different stages of pregnancy and post-delivery while continuing their regular HIV treatments.

Participant Groups

Group I: Doravirine Experimental Treatment 1 Intervention

100mg doravirine given by mouth once at each sampling visit.

Doravirine is already approved in United States, European Union for the following indications:

Approved in United States as Pifeltro for:

• HIV-1 infection

Approved in United States as Delstrigo for:

• HIV-1 infection

Approved in European Union as Delstrigo for:

• HIV-1 infection

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

Doravirine exposure in pregnant women is predicted to be significantly lower (by 55%) compared to nonpregnant women, which may lead to reduced effectiveness in treating HIV during pregnancy.

The study indicates that while doravirine crosses the placenta extensively, the predicted fetal exposure raises concerns about safety, emphasizing the need for monitoring and further clinical data on fetal effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments. Bukkems, VE., van Hove, H., Roelofsen, D., et al.[2022]

Doravirine is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for treating HIV-1 infection, available as both a single-agent tablet and a fixed-dose combination with other antiretroviral drugs.

It is specifically indicated for adults with no prior antiretroviral treatment and has received positive regulatory opinions in the USA and EU, highlighting its safety and efficacy for treatment-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doravirine: First Global Approval. Deeks, ED.[2021]

Doravirine shows promise as a treatment option for multidrug-resistant HIV-1, with 23% of cases demonstrating full susceptibility, compared to only 18% for etravirine and 5% for rilpivirine, based on a study of 22 participants with a long history of HIV treatment.

The study found that higher numbers of NNRTI mutations in the virus correlated with increased resistance to doravirine, but doravirine's effectiveness can still be predicted accurately using the Stanford HIVdb algorithm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Residual phenotypic susceptibility to doravirine in multidrug-resistant HIV-1 from subjects enrolled in the PRESTIGIO Registry. Saladini, F., Giammarino, F., Maggiolo, F., et al.[2023]

Doravirine, an HIV-1 NNRTI, is capable of crossing the placenta and accumulating in fetal tissue, with a fetal-to-maternal concentration ratio of 16%, indicating potential exposure to the fetus.

While doravirine may help reduce the risk of vertical HIV transmission, its accumulation in the placenta raises concerns about possible fetal toxicities, highlighting the need for further safety and efficacy studies in pregnant women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placental transfer of doravirine, a recent HIV-1 NNRTI in the ex vivo human cotyledon perfusion model. Lê, MP., Pencolé, L., Peytavin, G., et al.[2021]

In a Phase IIb trial involving 342 participants, doravirine 100 mg showed similar effectiveness to efavirenz 600 mg in reducing HIV-1 RNA levels, with 72.9% of doravirine recipients achieving viral suppression compared to 73.1% for efavirenz.

Doravirine was associated with significantly fewer central nervous system adverse events (26.9%) compared to efavirenz (47.2%), indicating a better safety profile for doravirine in this regard.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial. Gatell, JM., Morales-Ramirez, JO., Hagins, DP., et al.[2020]

In a study of 62 people living with HIV who switched to a single-tablet regimen containing doravirine, lamivudine, and tenofovir, 93.5% maintained viral suppression after 12 months, demonstrating the regimen's efficacy.

The treatment led to significant reductions in triglycerides and total cholesterol levels, indicating improved lipid profiles, while maintaining good tolerability with only minor weight gain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doravirine/lamivudine/tenofovir disoproxil fumarate in virologically suppressed people living with HIV: A real-life experience. Calza, L., Colangeli, V., Pensalfine, G., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Doravirine: First Global Approval. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Residual phenotypic susceptibility to doravirine in multidrug-resistant HIV-1 from subjects enrolled in the PRESTIGIO Registry. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Placental transfer of doravirine, a recent HIV-1 NNRTI in the ex vivo human cotyledon perfusion model. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Doravirine/lamivudine/tenofovir disoproxil fumarate in virologically suppressed people living with HIV: A real-life experience. [2023]