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

Maternal-fetal Infection Transmission Clinical Trial

— MONOGEST  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02738502
• Other study ID #: ANRS 168 MONOGEST
• Status: Completed
• Phase: Phase 2
• Start date: July 6, 2016
• Est. completion date: July 16, 2020

Study information

• Verified date: August 2021
• Source: ANRS, Emerging Infectious Diseases
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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) .

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. completion date: July 16, 2020
• Est. primary completion date: July 16, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Maternal-fetal Infection Transmission

Intervention

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.

Locations

Country	Name	City	State
France	CH Victor Dupouy	Argenteuil
France	Hôpital Jean Verdier	Bondy
France	Groupe hospitalier Pellegrin	Bordeaux
France	Hôpital Saint André	Bordeaux
France	Hôpital Antoine Béclère	Clamart
France	Hôpital Louis Mourier	Colombes
France	Hôpital Sud Francilien	Corbeil-essonnes
France	Hôpital Bicêtre	Le Kremlin Bicêtre
France	Hôpital de la croix Rousse	Lyon
France	Hôtel Dieu	Nantes
France	CHU Archet 1	Nice
France	Groupe hospitalier Cochin-Broca- Hôtel Dieu	Paris
France	HEGP	Paris
France	Hôpital Armand Trousseau	Paris
France	Hôpital Bichat - Claude Bernard	Paris
France	Hôpital la Pitié Salpétrière	Paris
France	Hôpital Lariboisiere	Paris
France	Hôpital Necker Enfant malades	Paris
France	Hôpital Tenon	Paris
France	CHU de Perpignan	Perpignan
France	CHU Rennes Hôpital Pontchaillou	Rennes
France	Hôpital Foch	Suresnes
France	CHU Toulouse	Toulouse

Sponsors (2)

Lead Sponsor	Collaborator
ANRS, Emerging Infectious Diseases	Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

References & Publications (7)

André-Schmutz I, Dal-Cortivo L, Six E, Kaltenbach S, Cocchiarella F, Le Chenadec J, Cagnard N, Cordier AG, Benachi A, Mandelbrot L, Azria E, Bouallag N, Luce S, Ternaux B, Reimann C, Revy P, Radford-Weiss I, Leschi C, Recchia A, Mavilio F, Cavazzana M, Blanche S. Genotoxic signature in cord blood cells of newborns exposed in utero to a Zidovudine-based antiretroviral combination. J Infect Dis. 2013 Jul 15;208(2):235-43. doi: 10.1093/infdis/jit149. Epub 2013 Apr 4. — View Citation

Arribas JR, Girard PM, Paton N, Winston A, Marcelin AG, Elbirt D, Hill A, Hadacek MB. Efficacy of protease inhibitor monotherapy vs. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials. HIV Med. 2016 May;17(5):358-67. doi: 10.1111/hiv.12348. Epub 2015 Dec 28. — View Citation

Hleyhel M, Goujon S, Delteil C, Vasiljevic A, Luzi S, Stephan JL, Reliquet V, Jannier S, Tubiana R, Dollfus C, Faye A, Mandelbrot L, Clavel J, Warszawski J, Blanche S; ANRS French Perinatal Cohort Study Group. Risk of cancer in children exposed to didanosine in utero. AIDS. 2016 May 15;30(8):1245-56. doi: 10.1097/QAD.0000000000001051. — View Citation

Lambert-Niclot S, Flandre P, Valantin MA, Soulie C, Fourati S, Wirden M, Sayon S, Pakianather S, Bocket L, Masquelier B, Dos Santos G, Katlama C, Calvez V, Marcelin AG. Similar evolution of cellular HIV-1 DNA level in darunavir/ritonavir monotherapy versus triple therapy in MONOI-ANRS136 trial over 96 weeks. PLoS One. 2012;7(7):e41390. doi: 10.1371/journal.pone.0041390. Epub 2012 Jul 25. — View Citation

Mandelbrot L, Tubiana R, Le Chenadec J, Dollfus C, Faye A, Pannier E, Matheron S, Khuong MA, Garrait V, Reliquet V, Devidas A, Berrebi A, Allisy C, Elleau C, Arvieux C, Rouzioux C, Warszawski J, Blanche S; ANRS-EPF Study Group. No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception. Clin Infect Dis. 2015 Dec 1;61(11):1715-25. doi: 10.1093/cid/civ578. Epub 2015 Jul 21. — View Citation

Tubiana R, Mandelbrot L, Le Chenadec J, Delmas S, Rouzioux C, Hirt D, Treluyer JM, Ekoukou D, Bui E, Chaix ML, Blanche S, Warszawski J; ANRS 135 PRIMEVA (Protease Inhibitor Monotherapy Evaluation) Study Group. Lopinavir/ritonavir monotherapy as a nucleoside analogue-sparing strategy to prevent HIV-1 mother-to-child transmission: the ANRS 135 PRIMEVA phase 2/3 randomized trial. Clin Infect Dis. 2013 Sep;57(6):891-902. doi: 10.1093/cid/cit390. Epub 2013 Jun 12. — View Citation

Valantin MA, Lambert-Niclot S, Flandre P, Morand-Joubert L, Cabiè A, Meynard JL, Ponscarme D, Ajana F, Slama L, Curjol A, Cuzin L, Schneider L, Taburet AM, Marcelin AG, Katlama C; MONOI ANRS 136 Study Group. Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study. J Antimicrob Chemother. 2012 Mar;67(3):691-5. doi: 10.1093/jac/dkr504. Epub 2011 Dec 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		At delivery (around 6 months after enrollment in the study).
Secondary	Plasma viral load (PVL) <50 copies / mL at delivery, Intention-to-treat (ITT) analysis		At delivery (around 6 months after enrollment in the study).
Secondary	Incidence of treatment changes for inefficacy, defined as PVL= 50 copies / mL at 2 successive controls.		Every month from Month1 up to the delivery.
Secondary	Incidence of treatment changes for intolerance / toxicity.		Every month from Month1 up to the delivery.
Secondary	Incidence of treatment changes for other reasons.		Every month from Month1 up to the delivery.
Secondary	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.	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.
Secondary	Factors associated with inefficacy (lymphocytes T CD4+ count).	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.
Secondary	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.	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.
Secondary	Factors associated with inefficacy (duration of undetectable plasma viral load before pregnancy).	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.
Secondary	Adverse pregnancy outcomes (preterm birth)	preterm birth : < 37 weeks gestational age from last menstrual period)	At delivery
Secondary	Adverse pregnancy outcomes (fetal loss)	Fetal loss defined as all stillbirths and spontaneous abortions before 22 weeks gestation	Every month from Month1 up to the delivery.
Secondary	Adverse pregnancy outcomes (low birth weight)	low birth weight < 3d percentile adjusted for gestational age and sex	At delivery
Secondary	Adverse pregnancy outcomes (low Apgar : < 7 at 5 minutes)		At delivery
Secondary	Adverse pregnancy outcomes (congenital malformations)	Malformations according to the European Surveillance of Congenital Anomalies (EUROCAT) classification)	At delivery
Secondary	Tolerance in children (hematological examinations).	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
Secondary	Tolerance in children (biochemical examinations).	AST and ALT, total bilirubin, lipase, sodium, potassium, urea, creatinine, calcium, phosphorus, lactates	At delivery, Day 3, 15, Month1, 3 and 6
Secondary	Interruption rate of postnatal nevirapine (NVP) within 2 weeks of life and patterns;		Day 3, Day15
Secondary	Any case of mother to child transmission would be considered a serious adverse event (SAE) and analyzed immediately.		Day 3, Month1, Month 3 and Month 6.