Prevention of Perinatal Transmission of HIV-1 Without Nucleoside Reverse Transcriptase Inhibitors (MONOGEST)

August 5, 2021 updated by: ANRS, Emerging Infectious Diseases

An Open-label Phase II Pilot Study of Prevention of Perinatal Transmission of HIV-1 Without Nucleoside Reverse Transcriptase Inhibitors

The overall goal is to study the feasibility of darunavir/ritonavir (DRV/r) monotherapy as treatment simplification (switch) in pretreated pregnant women, associated with neonatal prophylaxis with nevirapine, constituting a PMTCT strategy without any Nucleoside Reverse Transcriptase Inhibitor (NRTIs) .

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

90 participants will be enrolled and switch to darunavir monotherapy early in pregnancy (before 16 weeks of amenorrhea) in order to reduce exposure to the antiretroviral nucleos(t)ide analogues. The study treatment during the pregnancy is: darunavir 600 mg + ritonavir 100 mg 2 times 24 (DRV/r) monotherapy This regimen will be started after checking the tolerance of DRV/r 600 mg/100 mg twice daily (recommended dosage for pregnancy in French national recommendations) to replace whatever prior antiretrovirals (ARVs) were used, while maintaining the NRTI backbone for 2 weeks. Woman already receiving a triple drug combination with DRV/r will proceed directly to treatment simplification. If clinical tolerance of DRV/r is satisfactory after 2 weeks, nucleos(t)ides will be stopped. In case of intolerance, the treatment will be determined by the investigator but follow-up of the patient will continue.

No zidovudine will be administered at delivery in case of virological control, according to French Guidelines (Morlat Report 2015).

After delivery, the choice of maternal antiretrovial therapy (ART) is left to the discretion of the clinician and patient.

The mothers are followed up monthly until delivery and the last visit is planes at W4-W6 postpartum. Virological efficacy and safety will be assessed monthly.

In neonates, the prophylactic treatment, nevirapine oral solution, will be administrated as soon as possible in the first 12 hours of life and then for 14 days, once a day at a daily dose of 15 mg for a birthweight ≥ 2.5 kg ; 10 mg for a birthweight ≥ 2 kg and < 2.5 kg and 2 mg / kg for a birthweight < 2 kg (WHO Guidelines 2013 - French Guidelines, "Morlat Report" 2015).

Clinical and virological monitoring will be performed at Day 3, Day 15 in case of hospitalization, M1, M3 and M6.

Statistical Methods The analysis of the primary endpoint is the proportion of virological success (VL < 50 copies/mL at delivery among women remaining on DRV/r). All changes in antiretroviral therapy because of VL ≥ 50 copies/ml will be considered as failures. Women who change antiretroviral therapy for other reasons and/or when pregnancy outcome is before 22 weeks of amenorrhea and < 500g (non-viable pregnancy according to WHO) will be removed from the denominator.

Analysis of treatment changes, tolerance for the mother and child and factors associated with virological failure will be done by estimating percentages (categorical variables), average and median (continuous variables) with their intervals 95% confidence, overall and compared between the groups with virological success or failure per protocol (primary endpoint) or by intention to treat (secondary endpoint). The evolution of the parameters measured in children at birth, at 1, 3, and 6, months will be explored using non-parametric curves and compared between groups by repeated data taking into account the nonlinearity developments.

No interim analysis is planned.

Study Type

Interventional

Enrollment (Actual)

91

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Argenteuil, France, 95100
        • CH Victor Dupouy
      • Bondy, France, 93140
        • Hôpital Jean Verdier
      • Bordeaux, France, 33075
        • Hôpital Saint André
      • Bordeaux, France, 33000
        • Groupe Hospitalier Pellegrin
      • Clamart, France, 92140
        • Hôpital Antoine Béclère
      • Colombes, France, 92700
        • Hopital Louis Mourier
      • Corbeil-essonnes, France, 91106
        • Hôpital Sud Francilien
      • Le Kremlin Bicêtre, France, 94275
        • Hôpital Bicêtre
      • Lyon, France, 69307
        • Hôpital de La Croix Rousse
      • Nantes, France, 44093
        • Hotel Dieu
      • Nice, France, 06202
        • CHU Archet 1
      • Paris, France, 75018
        • Hôpital Bichat - Claude Bernard
      • Paris, France, 75010
        • Hopital Lariboisiere
      • Paris, France, 75020
        • Hopital Tenon
      • Paris, France, 75012
        • Hôpital Armand Trousseau
      • Paris, France, 75013
        • Hôpital La Pitié Salpêtrière
      • Paris, France, 75015
        • HEGP
      • Paris, France, 75015
        • Hôpital Necker Enfant Malades
      • Paris, France, 75014
        • Groupe hospitalier Cochin-Broca- Hôtel Dieu
      • Perpignan, France, 66046
        • CHU de Perpignan
      • Rennes, France, 35000
        • Chu Rennes Hopital Pontchaillou
      • Suresnes, France, 92151
        • Hopital Foch
      • Toulouse, France, 31059
        • CHU Toulouse

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Pregnant woman, under 15 weeks gestational age at screening
  • Documented Human Immunodeficiency Virus (HIV) HIV-1 infection (serology and/or plasma HIV RNA viral load)
  • Current treatment with at least two ARVs
  • Virological suppression for at least 12 months, defined by a PVL < 50 copies / mL. A blip (transiently ≥ 50 but < 400 copies/mL) will not be considered as an exclusion criterion, if it is followed by 2 successive controls with CV < 50 at least one month before enrollment
  • Plasma viral load < 50 copies/mL at pre-inclusion
  • CD4 ≥ 250 cells/mm3 at pre-inclusion
  • Informed written consent
  • Health care coverage

Inclusion criteria for the child :

  • Mother enrolled in the trial
  • Informed written consent by parents or legal guardians

Exclusion Criteria:

  • Infection by HIV-2
  • History of treatment failure and/or resistance with any Protease Inhibitor (PI). Treatment failure is defined by a viral replication (≥ 50 copies/mL) during antiretroviral treatment. An increasing CV due to treatment interruption will not be considered as a failure, providing that the absence of resistance mutations to at least one PI can be confirmed by genotyping.
  • Documented CD4 lymphocyte less than 200/mm3
  • Known intolerance to darunavir or ritonavir
  • Hepatitis B Virus (HBV) co-infection (HBs Ag-positive and/or detectable HBV DNA) on therapy with analogs (tenofovir, emtricitabine, lamivudine)
  • Known resistance of maternal viral strain to darunavir or nevirapine
  • Intended absence (travel abroad, moving ...)
  • Expected delivery in a maternity hospital not participating in the trial
  • Participation in the trial during previous pregnancy
  • Persons under guardianship or deprived of liberty by a judicial or administrative decision

Exclusion criteria for the child:

  • Refusal by parent (s) or legal guardian (s)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single Group
Intervention: Darunavir monotherapy darunavir/ritonavir 600 mg/100mg twice day in monotherapy.
Drug: darunavir monotherapy
darunavir 600 mg + ritonavir 100 mg 2 times 24 (DRV/r) monotherapy started after checking the tolerance of DRV/r600 mg/100 mg twice daily to replace whatever prior ARVs were used, while maintaining the NRTI backbone for 2 weeks.
Other Names:
  • ritonavir

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Success rate, defined by plasma viral load (PVL) <50 copies / mL near delivery with DRV/r monotherapy. Failure is defined as PVL > 50 copies / mL and/or change of antiretroviral therapy during pregnancy for PVL ≥ 50 copies / mL.
Time Frame: At delivery (around 6 months after enrollment in the study).
At delivery (around 6 months after enrollment in the study).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma viral load (PVL) <50 copies / mL at delivery, Intention-to-treat (ITT) analysis
Time Frame: At delivery (around 6 months after enrollment in the study).
At delivery (around 6 months after enrollment in the study).
Incidence of treatment changes for inefficacy, defined as PVL≥ 50 copies / mL at 2 successive controls.
Time Frame: Every month from Month1 up to the delivery.
Every month from Month1 up to the delivery.
Incidence of treatment changes for intolerance / toxicity.
Time Frame: Every month from Month1 up to the delivery.
Every month from Month1 up to the delivery.
Incidence of treatment changes for other reasons.
Time Frame: Every month from Month1 up to the delivery.
Every month from Month1 up to the delivery.
Factors associated with inefficacy (HIV-1 DNA). Inefficacy is defined as maternal plasma viral load > 50 copies/mL at delivery and/or change of antiretroviral therapy at any time from enrollment through delivery for plasma viral load > 50 copies/mL.
Time Frame: Every month from Month1 up to the delivery.
The following quantitative variables will be compared between women with inefficacy and those with virological success (plasma viral load < 50 copies/mL under darunavir/ritonavir) : HIV-1 DNA (total HIV-DNA log10 copies/million peripheral blood mononuclear cells by the ANRS technique).
Every month from Month1 up to the delivery.
Factors associated with inefficacy (lymphocytes T CD4+ count).
Time Frame: Every month from Month1 up to the delivery.
Inefficacy is defined as maternal plasma viral load > 50 copies/mL at delivery and/or change of antiretroviral therapy at any time from enrollment through delivery for plasma viral load > 50 copies/mL. The following quantitative variables will be compared between women with inefficacy and those with virological success (plasma viral load < 50 copies/mL under darunavir/ritonavir) : CD4+ lymphocyte count/microL.
Every month from Month1 up to the delivery.
Factors associated with inefficacy (CD4 nadir). Inefficacy is defined as maternal plasma viral load > 50 copies/mL at delivery and/or change of antiretroviral therapy at any time from enrollment through delivery for plasma viral load > 50 copies/mL.
Time Frame: Every month from Month1 up to the delivery.
The following quantitative variables will be compared between women with inefficacy and those with virological success (plasma viral load < 50 copies/mL under darunavir/ritonavir) : CD4+ lymphocyte/microL nadir.
Every month from Month1 up to the delivery.
Factors associated with inefficacy (duration of undetectable plasma viral load before pregnancy).
Time Frame: Every month from Month1 up to the delivery.
Inefficacy is defined as maternal plasma viral load > 50 copies/mL at delivery and/or change of antiretroviral therapy at any time from enrollment through delivery for plasma viral load > 50 copies/mL. The following quantitative variables will be compared between women with inefficacy and those with virological success (plasma viral load < 50 copies/mL under darunavir/ritonavir) : duration of undetectable plasma viral load before pregnancy (months).
Every month from Month1 up to the delivery.
Adverse pregnancy outcomes (preterm birth)
Time Frame: At delivery
preterm birth : < 37 weeks gestational age from last menstrual period)
At delivery
Adverse pregnancy outcomes (fetal loss)
Time Frame: Every month from Month1 up to the delivery.
Fetal loss defined as all stillbirths and spontaneous abortions before 22 weeks gestation
Every month from Month1 up to the delivery.
Adverse pregnancy outcomes (low birth weight)
Time Frame: At delivery
low birth weight < 3d percentile adjusted for gestational age and sex
At delivery
Adverse pregnancy outcomes (low Apgar : < 7 at 5 minutes)
Time Frame: At delivery
At delivery
Adverse pregnancy outcomes (congenital malformations)
Time Frame: At delivery
Malformations according to the European Surveillance of Congenital Anomalies (EUROCAT) classification)
At delivery
Tolerance in children (hematological examinations).
Time Frame: At delivery, Day 3, 15, Month1, 3 and 6
Hemoglobin, red blood cell count, white blood cell counts and differentials and platelet counts /microL, and mean corpuscular volume in fL
At delivery, Day 3, 15, Month1, 3 and 6
Tolerance in children (biochemical examinations).
Time Frame: At delivery, Day 3, 15, Month1, 3 and 6
AST and ALT, total bilirubin, lipase, sodium, potassium, urea, creatinine, calcium, phosphorus, lactates
At delivery, Day 3, 15, Month1, 3 and 6
Interruption rate of postnatal nevirapine (NVP) within 2 weeks of life and patterns;
Time Frame: Day 3, Day15
Day 3, Day15
Any case of mother to child transmission would be considered a serious adverse event (SAE) and analyzed immediately.
Time Frame: Day 3, Month1, Month 3 and Month 6.
Day 3, Month1, Month 3 and Month 6.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ANRS, Emerging Infectious Diseases

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France

Investigators

  • Study Director: François Dabis, Pr, MD, ANRS, Emerging Infectious Diseases

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 6, 2016

Primary Completion (Actual)

July 16, 2019

Study Completion (Actual)

July 16, 2020

Study Registration Dates

First Submitted

March 23, 2016

First Submitted That Met QC Criteria

April 11, 2016

First Posted (Estimate)

April 14, 2016

Study Record Updates

Last Update Posted (Actual)

August 6, 2021

Last Update Submitted That Met QC Criteria

August 5, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ANRS 168 MONOGEST

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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