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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Maternal-fetal Infection Transmission

Intervention / Treatment
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* Drug: darunavir monotherapy


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Group<br>Intervention: Darunavir monotherapy darunavir/ritonavir 600 mg/100mg twice day in monotherapy. | Drug: darunavir monotherapy<br>* 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.<br>* Other names: ritonavir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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. |  | 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 |  | 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. |  | Every month from Month1 up to the delivery. | 
| Incidence of treatment changes for intolerance / toxicity. |  | Every month from Month1 up to the delivery. | 
| Incidence of treatment changes for other reasons. |  | 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. | 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). | 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. | 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). | 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) | preterm birth : < 37 weeks gestational age from last menstrual period) | At delivery | 
| 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. | 
| Adverse pregnancy outcomes (low birth weight) | low birth weight < 3d percentile adjusted for gestational age and sex | At delivery | 
| Adverse pregnancy outcomes (low Apgar : < 7 at 5 minutes) |  | At delivery | 
| Adverse pregnancy outcomes (congenital malformations) | Malformations according to the European Surveillance of Congenital Anomalies (EUROCAT) classification) | At delivery | 
| 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 | 
| 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 | 
| Interruption rate of postnatal nevirapine (NVP) within 2 weeks of life and patterns; |  | Day 3, Day15 | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, prevention of mother-to-child transmission, Ritonavir boosted darunavir monotherapy