Dolutegravir in Pregnant HIV Mothers and Their Neonates (DolPHIN-2)

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)

Study Overview

• Status: Completed
• Conditions: Pregnancy Related; HIV-1-infection
• Intervention / Treatment: Drug: Dolutegravir; Drug: Standard of Care (EFV + 2 NRTI backbone)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 268
• Phase: Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa
      • University of Cape Town
• Uganda
  • Kampala, Uganda
    • Infectious Diseases Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Women aged 18 years or older
4. Pregnant ( ≥28 weeks gestation by best available gestation estimation)
5. Untreated HIV infection in late pregnancy

Exclusion Criteria:

1. Received any antiretroviral drugs in previous 12 months
2. Ever received integrase inhibitors
3. 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
4. Serum haemoglobin <8.0 g/dl
5. eGFR<50 ml/min*
6. 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).
7. 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).
8. 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
9. Paternal objection for infant participation in DTG arm (where disclosure has taken - applies to Uganda site only
10. Medical, psychiatric or obstetric condition that might affect participation in the study based on investigator judgement
11. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dolutegravir; 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; Patients randomized to the study drug will be commenced on an antiretroviral regimen comprising DTG 50mg once daily in combination with 2 NRTIs
Active Comparator: Standard of Care (EFV + 2 NRTI backbone); 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); Patients randomized to receive standard of care will receive the currently used antiretroviral regimens in keeping with national policy.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drug toxicities as defined by DAIDS criteria	Safety questionnaire	Each study visit up to 72 weeks postpartum
Drug toxicities as defined by DAIDS criteria	CBC	Each study visit up to 72 weeks postpartum
Drug toxicities as defined by DAIDS criteria	Serum creatinine (mg/dL)	Each study visit up to 72 weeks postpartum
Drug toxicities as defined by DAIDS criteria	ALT (U/mL)	Each study visit up to 72 weeks postpartum
Drug toxicities as defined by DAIDS criteria	Blood urea nitrogen (mg/dL)	Each study visit up to 72 weeks postpartum
Drug toxicities as defined by DAIDS criteria	Creatine phosphokinase (U/mL)	Each study visit up to 72 weeks postpartum
Safety endpoint: Maternal mental health (Edinburgh Postnatal Depression Scale)	Edinburgh Postnatal Depression Scale	Enrolment, 4 weeks after ART initiation, every postnatal visit up to 72 weeks postpartum
Safety endpoint: Maternal mental health (Hospital Anxiety and Depression Scale)	Hospital Anxiety and Depression Scale	Enrolment, 4 weeks after ART initiation, every postnatal visit up to 72 weeks postpartum
Safety of DTG in infant: Birth outcomes (Surface examination for anomalies)	Surface examination for anomalies	At birth
Safety of DTG in infant: Birth outcomes (Ballard Score for Maturity)	Ballard Score for Maturity	At birth
Safety of DTG in infant: Birth outcomes (Weight)	Weight	At birth
Safety of DTG in infant: Birth outcomes (Length)	Length	At birth
Safety of DTG in infant: Growth and development (Infant gross motor screening tool)	Infant gross motor screening tool	24, 48 and 72 weeks postpartum
Safety and tolerability of DTG exposure to infant: Maternal report (Safety questionnaire)	Safety questionnaire	Delivery and all postnatal follow-up to 72 weeks
Safety of DTG exposure to infant (Blood glucose)	Blood glucose	Delivery and 6 weeks postpartum
Safety of DTG exposure to infant	ALT (U/mL)	6 weeks postpartum
Safety of DTG exposure to infant	Blood urea nitrogen (mg/dL)	6 weeks postpartum
Safety of DTG exposure to infant	Serum creatinine (mg/dL)	6 weeks postpartum

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: Radboud University Medical Center; University of Cape Town; UNITAID; Liverpool School of Tropical Medicine; Infectious Diseases Institute, Uganda
• Investigators: Study Chair: Saye H Khoo, University of Liverpool

Publications and helpful links

General Publications

• Malaba TR, Nakatudde I, Kintu K, Colbers A, Chen T, Reynolds H, Read L, Read J, Stemmet LA, Mrubata M, Byrne K, Seden K, Twimukye A, Theunissen H, Hodel EM, Chiong J, Hu NC, Burger D, Wang D, Byamugisha J, Alhassan Y, Bokako S, Waitt C, Taegtmeyer M, Orrell C, Lamorde M, Myer L, Khoo S; DolPHIN-2 Study Group. 72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study. Lancet HIV. 2022 Aug;9(8):e534-e543. doi: 10.1016/S2352-3018(22)00173-4.
• Ochanda PN, Lamorde M, Kintu K, Wang D, Chen T, Malaba T, Myer L, Waitt C, Reynolds H, Khoo S. A randomized comparison of health-related quality of life outcomes of dolutegravir versus efavirenz-based antiretroviral treatment initiated in the third trimester of pregnancy. AIDS Res Ther. 2022 Jun 7;19(1):24. doi: 10.1186/s12981-022-00446-3.
• Kintu K, Malaba TR, Nakibuka J, Papamichael C, Colbers A, Byrne K, Seden K, Hodel EM, Chen T, Twimukye A, Byamugisha J, Reynolds H, Watson V, Burger D, Wang D, Waitt C, Taegtmeyer M, Orrell C, Lamorde M, Myer L, Khoo S; DolPHIN-2 Study Group. Dolutegravir versus efavirenz in women starting HIV therapy in late pregnancy (DolPHIN-2): an open-label, randomised controlled trial. Lancet HIV. 2020 May;7(5):e332-e339. doi: 10.1016/S2352-3018(20)30050-3.

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2018
• Primary Completion (Actual): October 20, 2020
• Study Completion (Actual): September 5, 2023

Study Registration Dates

• First Submitted: July 28, 2017
• First Submitted That Met QC Criteria: August 9, 2017
• First Posted (Actual): August 15, 2017

Study Record Updates

• Last Update Posted (Actual): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 10, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MTCT; Pregnancy; Africa; Antiretroviral
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: DolPHIN-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No