Clinical trial NCT02738502: Prevention of Perinatal Transmission of HIV-1 Without Nucleoside Reverse Transcriptase Inhibitors
Official title: An Open-label Phase II Pilot Study of Prevention of Perinatal Transmission of HIV-1 Without Nucleoside Reverse Transcriptase Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Maternal-fetal Infection Transmission
Keywords: HIV
prevention of mother-to-child transmission
Ritonavir boosted darunavir monotherapy
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2016-04-14
Enrollment: 91
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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) .

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.

Eligibility criteria: 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)

Primary outcomes:
measure: 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.
timeFrame: At delivery (around 6 months after enrollment in the study).
Secondary outcomes:
measure: Plasma viral load (PVL) <50 copies / mL at delivery, Intention-to-treat (ITT) analysis
timeFrame: At delivery (around 6 months after enrollment in the study).
measure: Incidence of treatment changes for inefficacy, defined as PVL≥ 50 copies / mL at 2 successive controls.
timeFrame: Every month from Month1 up to the delivery.
measure: Incidence of treatment changes for intolerance / toxicity.
timeFrame: Every month from Month1 up to the delivery.
measure: Incidence of treatment changes for other reasons.
timeFrame: Every month from Month1 up to the delivery.
measure: 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.
timeFrame: Every month from Month1 up to the delivery.
measure: Factors associated with inefficacy (lymphocytes T CD4+ count).
timeFrame: Every month from Month1 up to the delivery.
measure: 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.
timeFrame: Every month from Month1 up to the delivery.
measure: Factors associated with inefficacy (duration of undetectable plasma viral load before pregnancy).
timeFrame: Every month from Month1 up to the delivery.
measure: Adverse pregnancy outcomes (preterm birth)
timeFrame: At delivery
measure: Adverse pregnancy outcomes (fetal loss)
timeFrame: Every month from Month1 up to the delivery.
measure: Adverse pregnancy outcomes (low birth weight)
timeFrame: At delivery
measure: Adverse pregnancy outcomes (low Apgar : < 7 at 5 minutes)
timeFrame: At delivery
measure: Adverse pregnancy outcomes (congenital malformations)
timeFrame: At delivery
measure: Tolerance in children (hematological examinations).
timeFrame: At delivery, Day 3, 15, Month1, 3 and 6
measure: Tolerance in children (biochemical examinations).
timeFrame: At delivery, Day 3, 15, Month1, 3 and 6
measure: Interruption rate of postnatal nevirapine (NVP) within 2 weeks of life and patterns;
timeFrame: Day 3, Day15
measure: Any case of mother to child transmission would be considered a serious adverse event (SAE) and analyzed immediately.
timeFrame: Day 3, Month1, Month 3 and Month 6.
Other outcomes:
Locations:
city: Argenteuil
country: France
facility: CH Victor Dupouy
city: Bondy
country: France
facility: Hôpital Jean Verdier
city: Bordeaux
country: France
facility: Groupe hospitalier Pellegrin
city: Bordeaux
country: France
facility: Hôpital Saint André
city: Clamart
country: France
facility: Hôpital Antoine Béclère
city: Colombes
country: France
facility: Hôpital Louis Mourier
city: Corbeil-essonnes
country: France
facility: Hôpital Sud Francilien
city: Le Kremlin Bicêtre
country: France
facility: Hôpital Bicêtre
city: Lyon
country: France
facility: Hôpital de la croix Rousse
city: Nantes
country: France
facility: Hôtel Dieu
city: Nice
country: France
facility: CHU Archet 1
city: Paris
country: France
facility: Hôpital Lariboisiere
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Paris
country: France
facility: Hôpital la Pitié Salpétrière
city: Paris
country: France
facility: Groupe hospitalier Cochin-Broca- Hôtel Dieu
city: Paris
country: France
facility: HEGP
city: Paris
country: France
facility: Hôpital Necker Enfant malades
city: Paris
country: France
facility: Hôpital Bichat - Claude Bernard
city: Paris
country: France
facility: Hôpital Tenon
city: Perpignan
country: France
facility: CHU de Perpignan
city: Rennes
country: France
facility: CHU Rennes Hôpital Pontchaillou
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse
country: France
facility: CHU Toulouse
Study officials:
affiliation: ANRS, Emerging Infectious Diseases
name: François DABIS, Pr, MD
role: STUDY_DIRECTOR
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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.
citation: Valantin MA, Lambert-Niclot S, Flandre P, Morand-Joubert L, Cabie 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.
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.