Dolutegravir in Pregnant HIV Mothers and Their Neonates

Study Overview
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Brief Summary
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To evaluate dolutegravir (DTG) efficacy in women who present with untreated HIV in late pregnancy. An open-label, multi-centre randomised controlled trial of DTG vs efavirenz-based regimens for women commencing cART in late pregnancy. HIV positive pregnant women presenting with untreated HIV infection in late (≥28 weeks gestation) pregnancy will be randomised 1:1 to receive DTG (50mg once daily) + 2 nucleoside reverse transcriptase inhibitors (NRTIs) or EFV + 2 NRTIs (SoC)

Detailed Description
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This is an open-label, randomised controlled trial of DTG versus EFV -based regimens for 250 women commencing cART in late pregnancy, randomised 1:1 to DTG vs EFV-based cART. The purpose of this study is to inform treatment guidelines and for the first time specifically address the treatment needs of this group of women- hence the trial is powered for superiority over EFV. The primary endpoints is maternal VL at delivery, with secondary endpoints including safety and tolerability of DTG in both mother and infant, VL decline in breast milk, development of drug resistance, pharmacokinetics of DTG in mother-infant pairs, pharmacogenomics factors relating to efficacy or toxicity of DTG, and MTCT of HIV up to 72 weeks postpartum. Two sites have been selected - Infectious Diseases Institute, Makerere University, Kampala, Uganda and the University of Cape Town, South Africa - both have a strong track record of successfully delivering collaborative multidisciplinary research in PMTCT. Furthermore, health economics analysis to examine costs and cost-effectiveness of DTG in late-presenting pregnant women will be conducted The desired outcome of this project is to establish high quality evidence and operational guidance for use of DTG in late pregnancy. Late-presenting HIV-infected pregnant women are an important, but neglected group of vulnerable individuals in whom a randomised controlled intervention of HIV treatment has never previously been undertaken. This work will be done in relationship with WHO and the Clinton Health Access Initiative to ensure successful delivery of the project objectives.

Official Title
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Dolutegravir in Pregnant HIV Mothers and Their Neonates

Conditions
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HIV-1-infection, Pregnancy Related

Intervention / Treatment
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* Drug: Dolutegravir
* Drug: Standard of Care (EFV + 2 NRTI backbone)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Women aged 18 years or older Pregnant ( ≥28 weeks gestation by best available gestation estimation) Untreated HIV infection in late pregnancy Exclusion Criteria: Received any antiretroviral drugs in previous 12 months Ever received integrase inhibitors Previous documented failure of an NNRTI-containing ART regimen, previous EFV-associated toxicity or other history of ARV use that would preclude randomisation based on investigator judgement Serum haemoglobin <8.0 g/dl eGFR<50 ml/min* Elevations in serum levels of alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or ALT >3xULN and bilirubin >2xULN (with >35% direct bilirubin). History or clinical suspicion of unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hyperbilirubinaemia, oesophageal or gastric varices or persistent jaundice). Severe pre-eclampsia (e.g. HELLP), or other pregnancy related events such as renal or liver abnormalities (e.g. grade 2 or above proteinuria,, total bilirubin, ALT or AST)* at the time of enrolment Paternal objection for infant participation in DTG arm (where disclosure has taken - applies to Uganda site only Medical, psychiatric or obstetric condition that might affect participation in the study based on investigator judgement Receiving any of the following medications (current or within past 2 weeks): anti-epileptic drugs, TB therapy, or other drugs known to significantly interact with either DTG or EFV

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An open-label, multi-centre randomised controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dolutegravir<br>Dolutegravir group (DTG+2 NRTIs) - to make best comparison with standard of care, these NRTIs should be those recommended by national policy. Participants randomized to the study drug will be commenced on an antiretroviral regimen comprising DTG 50mg once daily in combination with 2 NRTIs | Drug: Dolutegravir<br>* Patients randomized to the study drug will be commenced on an antiretroviral regimen comprising DTG 50mg once daily in combination with 2 NRTIs<br>|
| Active Comparator: Standard of Care (EFV + 2 NRTI backbone)<br>Participants randomized to receive standard of care will receive the currently used antiretroviral regimens in keeping with national policy (EFV + 2NRTIs at both study sites). | Drug: Standard of Care (EFV + 2 NRTI backbone)<br>* Patients randomized to receive standard of care will receive the currently used antiretroviral regimens in keeping with national policy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV Viral Load at Delivery | <50 copies/ mL | by delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma viral load | <1000 copies/ mL | By delivery | 
| Maternal viral load to 48 weeks | Proportion <50 and <1000 copies/ mL | 48 weeks postpartum | 
| Maternal viral load to 72 weeks | Proportion <50 and <1000 copies/ mL | 72 weeks postpartum | 
| Occurrence of MTCT | Proportion of infants with HIV infection | 48 weeks postpartum | 
| Occurrence of MTCT | Proportion of infants with HIV infection | 72 weeks postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MTCT, Antiretroviral, Pregnancy, Africa