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

Conditions

HIV-1 Infection

Keywords

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

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.

Detailed description

This is an open label randomised, non-inferiority (10% non-inferiority margin), phase 3 study to assess the efficacy and safety of DTG (50 mg once daily \[QD\]) administered in combination with TAF (25 mg QD) and FTC (200 mg QD) compared to DTG (50 mg QD) administered in combination with TDF (300 mg QD) and FTC (200 mg QD) and compared to 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. Approximately 1110 male and female patients infected with HIV-1 who are eligible for first-line ART will be randomly assigned in a 1:1:1 ratio (approximately 370 patients per treatment group) to Treatment Group 1 (DTG + TAF + FTC) or Treatment Group 2 (DTG + TDF + FTC) or Treatment Group 3 (EFV + TDF + FTC). To ensure adequate representation of adolescents (12 - 18 years) in any treatment group, randomisation will be stratified according to age greater or less than 18 years. The study includes screening and baseline visits, 8 study visits from Week 4 to Week 84, and a preliminary end of study visit at Week 96. The study will then take patients on Treatment Group 1 (DTG + TAF + FTC) or Treatment Group 2 (DTG + TDF + FTC) or Treatment Group 3 (EFV + TDF + FTC), who have completed 96 weeks successfully, and follow them to 192 weeks, with visits every 24 weeks after enrolment to 192 weeks. Study medication pill counts will be performed at each follow-up visit.

J. Taylor, Gary Maartens, Simiso Sokhela, Nomathemba Chandiwana, Godspower Akpomiemie et al. (7 authors)

Southern African Journal of HIV Medicine2025-03-18

10.4102/sajhivmed.v26i1.1661

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

Jennifer Manne‐Goehler, June Fabian, Simiso Sokhela, Godspower Akpomiemie, Nicholas E. Rahim et al. (10 authors)

Journal of the International AIDS Society2024-07-013 citations

10.1002/jia2.26268

Determinants of early change in serum creatinine after initiation of dolutegravir‐based antiretroviral therapy in South Africa

Rephaim Mpofu, Aida N. Kawuma, Roeland E. Wasmann, Godspower Akpomiemie, Nomathemba Chandiwana et al. (14 authors)

British Journal of Clinical Pharmacology2024-02-084 citations

10.1111/bcp.16009

Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV

Zinhle Cindi, Aida N. Kawuma, Gary Maartens, Yuki Bradford, Simiso Sokhela et al. (13 authors)

Pharmacogenetics and Genomics2023-03-063 citations

10.1097/fpc.0000000000000495

Limited Weight Impact After Switching From Boosted Protease Inhibitors to Dolutegravir in Persons With Human Immunodeficiency Virus With High Cardiovascular Risk: A Post Hoc Analysis of the 96-Week NEAT-022 Randomized Trial

Laura Waters, Lambert Assoumou, Ana González-Cordón, Stefano Rusconi, Peré Domingo et al. (100 authors)

Clinical Infectious Diseases2022-10-1815 citations

10.1093/cid/ciac827

Point-of-Care Tenofovir Urine Testing for the Prediction of Treatment Failure and Drug Resistance During Initial Treatment for Human Immunodeficiency Virus Type 1 (HIV-1) Infection

Lucas E. Hermans, Chijioke N. Umunnakwe, Samanta Tresha Lalla‐Edward, Shane Hebel, Hugo A. Tempelman et al. (8 authors)

Clinical Infectious Diseases2022-09-1921 citations

10.1093/cid/ciac755

Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir-Containing and Tenofovir-Containing Regimens

Zinhle Cindi, Gary Maartens, Yuki Bradford, François Venter, Simiso Sokhela et al. (8 authors)

JAIDS Journal of Acquired Immune Deficiency Syndromes2021-02-2710 citations

10.1097/qai.0000000000002661

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Mark J. Siedner, Michelle Moorhouse, Bryony Simmons, Túlio de Oliveira, Richard Lessells et al. (13 authors)

Nature Communications2020-12-0181 citations

10.1038/s41467-020-19801-x

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.

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.

2020-10-01196 citations

10.1016/s2352-3018(20)30241-1

Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV

François Venter, Michelle Moorhouse, Simiso Sokhela, Lee Fairlie, Nkuli Mashabane et al. (19 authors)

New England Journal of Medicine2019-07-24681 citations

10.1056/nejmoa1902824

Interventions

DRUGDolutegravir

DTG 50mg Oral Tablet once daily

DRUGTenofovir Alafenamide

TAF/FTC 25/200mg Oral Tablet once daily

DRUGTruvada

DRUGAtripla

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

Healthy volunteers

No

Inclusion criteria

1. Age ≥ 12 years and ≥ 40 kg 2. Documented laboratory diagnosis of infection with HIV-1 (positive enzyme-linked immunosorbent assay HIV-1 antibody test) at screening 3. Plasma HIV-1 RNA (VL) ≥ 500 copies/mL 4. All pre-existing medical or laboratory abnormalities must be deemed to be stable by the investigator prior to study enrolment 5. 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 6. 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: 1. Previously enrolled on the ADVANCE study, and followed to week 96 (including those on post-trial access) 2. 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.

Exclusion criteria

1. Previously received more than 30 days of treatment with any form of antiretroviral therapy (ART) or 2. Received any antiretrovirals within the last 6 months 3. Women who are pregnant at the time of the screening or baseline visit 4. Active tuberculosis and/or are on antituberculous therapy at the time of the baseline visit 5. 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 6. Clinically unstable, in the investigator's opinion 7. Current history of drug or alcohol abuse that, in the opinion of the investigator, may be an impediment to patient adherence to the protocol 8. 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 9. Have a strong likelihood of relocating far enough to make access to the study site difficult 10. History or presence of allergy to the study drugs or their components 11. 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: 1. 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 2. Clinically unstable, in the opinion of the investigator 3. Have a strong likelihood of relocating far enough to make access to the study site difficult.

Design outcomes

Primary

Measure	Time frame	Description
Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48	48 weeks	The proportion of participants with undetectable plasma HIV-1 RNA levels at Week 48, will be calculated for each treatment group and summarised.

Secondary

Measure	Time frame	Description
Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 192	192 weeks	• Participants with undetectable plasma HIV-1 RNA levels will be defined as those with plasma RNA levels of \< 200 copies/mL. Successes/responders will be defined as those participants on each regimen with undetectable plasma HIV-1 RNA levels at Week 192.
Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48, 96, 144 and 192	192 weeks	Using FDA snapshot algorithm
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	Time to virologic failure will be modelled by Cox regression.
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	Individual patient plasma HIV-1 RNA levels will be summarised and listed by treatment and visit, together with changes from screening/enrolment plasma HIV-1 RNA levels. Observations (linear and log transformed) will also be presented graphically, over time, in the form of line plots.
Change from baseline in plasma CD4 levels at each visit	At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192	Individual patient CD4 counts will be summarised and listed by treatment and visit, together with changes from screening/enrolment CD4 values. Observations (linear and log transformed) will also be presented graphically, over time, in the form of line plots.

Other

Measure	Time frame	Description
Analysis of PK data in those becoming pregnant	Monthly	Participants in treatment groups 1 and 2 who develop TB during the study will have DTG trough levels (ng/mL) measures will be measured in control non-pregnantsubjects in a 3:1 ratio.
Virological efficacy in the 12 - 18 year age group	Week 48, 96	Proportion of patients with undetectable plasma HIV-1 RNA levels (\< 50 copies/mL) at Week 48 and 96 in a subgroup analysis of this age-range
Analysis of PK data in those developing TB	Over course of TB treatment in those developing TB, during 3 regular scheduled visits	Participants in treatment groups 1 and 2 who develop TB during the study will have DTG trough levels (ng/mL) measured at routine scheduled three visits. Trough levels will also be measured in control subjects (without TB coinfection) in a 3:1 ratio.
Nature and frequency of adverse events	Week 48, 96, 144, 192	A summary table will be presented, summarised by treatment, SOC and preferred term including the number of patients dosed in treatment group and number and percentage of subjects with AEs.

Countries

South Africa

Outcome results

None listed