ADVANCE Study of DTG + TAF + FTC vs DTG + TDF + FTC and EFV + TDF+FTC in First-line Antiretroviral Therapy

NCT03122262 | Completed Phase 3 DMC

• 1 other identifier: WRHI060
• Study Type: interventional
• Target: 1,110
• Locations: 1 country
• Sites: 4

Brief Summary

This is a non-inferiority (10% non-inferiority margin), study to assess the efficacy and safety of dolutegravir, DTG (50 mg once daily \[QD\]) administered in combination with tenofovir alafenamide fumarate, TAF (25 mg QD) and emtricitabine, FTC (200 mg QD) compared to DTG (50 mg QD) administered in combination with tenofovir disoproxil fumarate, TDF (300 mg QD) and FTC (200 mg QD) and compared to efavirenz, EFV (600 mg QD) administered in combination with TDF (300 mg QD) and FTC (200 mg QD) through 96 weeks in patients with HIV-1 starting first-line ART.

Conditions

HIV-1 Infection

Keywords

Antiretroviral Agents, first-line antiretroviral therapy; dolutegravir; Tenofovir alafenamide

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48

  The proportion of participants with undetectable plasma HIV-1 RNA levels at Week 48, will be calculated for each treatment group and summarised.

  48 weeks

Secondary Outcomes (5)

• Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48, 96, 144 and 192

  192 weeks

• Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 192

  192 weeks

• Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥ 1000 copies/mL at week 12 - 24 or ≥ 200 copies/mL at or after week 24)

  24 weeks

• Change from baseline in plasma HIV-1 RNA levels at each visit

  At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192

• Change from baseline in plasma CD4 levels at each visit

  At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192

Other Outcomes (4)

• Nature and frequency of adverse events

  Week 48, 96, 144, 192

• Analysis of PK data in those developing TB

  Over course of TB treatment in those developing TB, during 3 regular scheduled visits

• Analysis of PK data in those becoming pregnant

  Monthly

Study Arms (3)

Tenofovir Alafenamide

ACTIVE COMPARATOR

Descovy: Tenofivir alafenamide tablets 25mg daily, Emtricitabine 200mg daily

Drug: Dolutegravir; Drug: Tenofovir Alafenamide

Dolutegravir

ACTIVE COMPARATOR

Dolutegravir 50mg daily, Truvada 500mg daily

Drug: Dolutegravir; Drug: Truvada

Atripla

ACTIVE COMPARATOR

Atripla: Efavirenz 600mg daily, Tenofovir Disoproxil Fumarate 300mg daily, Emtricitabine 200mg daily

Drug: Atripla

Interventions

Dolutegravir DRUG

DTG 50mg Oral Tablet once daily

Also known as: Tivicay

Dolutegravir; Tenofovir Alafenamide

Tenofovir Alafenamide DRUG

TAF/FTC 25/200mg Oral Tablet once daily

Also known as: Descovy

Tenofovir Alafenamide

Truvada DRUG

Also known as: TDF/FTC 300/200mg Oral Tablet

Dolutegravir

Atripla DRUG

Also known as: EFV/TDF/FTC 600/200/300mg Oral Tablet

Atripla

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 12 years and ≥ 40 kg
• Documented laboratory diagnosis of infection with HIV-1 (positive enzyme-linked immunosorbent assay HIV-1 antibody test) at screening
• Plasma HIV-1 RNA (VL) ≥ 500 copies/mL
• All pre-existing medical or laboratory abnormalities must be deemed to be stable by the investigator prior to study enrolment
• Calculated creatinine clearance (CrCl) \> 60 mL/min (Cockcroft-Gault formula) in \> 18 years old OR \> 80 mL/min (modified Cockcroft-Gault) in ≤ 18 years old
• Ability to comprehend the full nature and purpose of the study, in the opinion of the investigator, and to comply with the requirements of the entire study.
• To enrol in extension post-96 weeks:
• Each patient must meet all of the following criteria to be enrolled in this study:
• Previously enrolled on the ADVANCE study, and followed to week 96 (including those on post-trial access)
• Ability to comprehend the full nature and purpose of the study, including the extended timeline, in the opinion of the investigator, and to comply with the requirements of the entire study.

You may not qualify if:

• Previously received more than 30 days of treatment with any form of antiretroviral therapy (ART) or
• Received any antiretrovirals within the last 6 months
• Women who are pregnant at the time of the screening or baseline visit
• Active tuberculosis and/or are on antituberculous therapy at the time of the baseline visit
• Taking and cannot discontinue prohibited concomitant medications listed in 7.3 at least 2 weeks prior to the baseline visit and for the duration of the study period
• Clinically unstable, in the investigator's opinion
• Current history of drug or alcohol abuse that, in the opinion of the investigator, may be an impediment to patient adherence to the protocol
• Patients who participated in a study with an investigational drug within 60 days of screening or who are currently receiving treatment with any other investigational drug or device may be ineligible to participate. This is an investigator decision
• Have a strong likelihood of relocating far enough to make access to the study site difficult
• History or presence of allergy to the study drugs or their components
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); Child-Pugh C.
• To enrol in extension post-96 weeks:
• Patients meeting the following criteria will be excluded from the study:
• HbA1c, lipids and blood pressures that are not responding to treatment, in the opinion of the investigator and in consultation with the principal investigator, justifying substitution of DTG or TAF
• Clinically unstable, in the opinion of the investigator

Sponsors & Collaborators

• Professor Francois Venter: lead

Study Sites (4)

Shandukani Research Centre

Johannesburg, Gauteng, 2001, South Africa

Location

Charlotte Maxeke Johannesburg Academic Hospital

Johannesburg, Gauteng, 2196, South Africa

Location

Sunnyside Office Park

Johannesburg, Gauteng, South Africa

Location

Wits RHI Yeoville Clinic

Johannesburg, Gauteng, South Africa

Location

Related Publications (6)

• Manne-Goehler J, Fabian J, Sokhela S, Akpomiemie G, Rahim N, Lalla-Edward ST, Brennan AT, Siedner MJ, Hill A, Venter WDF. Blood pressure increases are associated with weight gain and not antiretroviral regimen or kidney function: a secondary analysis from the ADVANCE trial in South Africa. J Int AIDS Soc. 2024 Jul;27(7):e26268. doi: 10.1002/jia2.26268.

  PMID: 38978403 DERIVED

• Cindi Z, Kawuma AN, Maartens G, Bradford Y, Sokhela S, Chandiwana N, Venter WDF, Wasmann RE, Denti P, Wiesner L, Ritchie MD, Haas DW, Sinxadi P. Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV. Pharmacogenet Genomics. 2023 Jun 1;33(4):79-87. doi: 10.1097/FPC.0000000000000495. Epub 2023 Mar 6.

  PMID: 37098852 DERIVED

• Cindi Z, Maartens G, Bradford Y, Venter WDF, Sokhela S, Chandiwana NC, Haas DW, Sinxadi P. Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir-Containing and Tenofovir-Containing Regimens. J Acquir Immune Defic Syndr. 2021 Jul 1;87(3):1002-1009. doi: 10.1097/QAI.0000000000002661.

  PMID: 33625064 DERIVED

• Siedner MJ, Moorhouse MA, Simmons B, de Oliveira T, Lessells R, Giandhari J, Kemp SA, Chimukangara B, Akpomiemie G, Serenata CM, Venter WDF, Hill A, Gupta RK. Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase. Nat Commun. 2020 Dec 1;11(1):5922. doi: 10.1038/s41467-020-19801-x.

  PMID: 33262331 DERIVED

• Venter WDF, Sokhela S, Simmons B, Moorhouse M, Fairlie L, Mashabane N, Serenata C, Akpomiemie G, Masenya M, Qavi A, Chandiwana N, McCann K, Norris S, Chersich M, Maartens G, Lalla-Edward S, Vos A, Clayden P, Abrams E, Arulappan N, Hill A. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV. 2020 Oct;7(10):e666-e676. doi: 10.1016/S2352-3018(20)30241-1.

  PMID: 33010240 DERIVED

• Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane N, Masenya M, Serenata C, Akpomiemie G, Qavi A, Chandiwana N, Norris S, Chersich M, Clayden P, Abrams E, Arulappan N, Vos A, McCann K, Simmons B, Hill A. Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV. N Engl J Med. 2019 Aug 29;381(9):803-815. doi: 10.1056/NEJMoa1902824. Epub 2019 Jul 24.

  PMID: 31339677 DERIVED

MeSH Terms

Interventions

dolutegravir; tenofovir alafenamide; emtricitabine tenofovir alafenamide; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Tablets; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Intervention Hierarchy (Ancestors)

Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations; Dosage Forms; Oxazines

Study Officials

• Willem Daniel Francois Venter, FCP (SA)

  Wits Reproductive Health & HIV Institute, University of the Witswatersrand

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 11, 2016
• First Posted: April 20, 2017
• Study Start: January 16, 2017
• Primary Completion: April 30, 2022
• Study Completion: July 29, 2022
• Last Updated: February 8, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Immediately following publication
• Access Criteria: Anyone who wishes to access the data

Locations

ZA (4)