B-free Multistage Trial (B-free)

Booster-free Antiretroviral Therapy for Persons Living With HIV and Multidrug Resistance: A Multicentre Multi-stage Randomized Trial

The primary objective of the study is to evaluate the efficacy of a booster-free regimen including DOR/DTG/3TC among HIV-suppressed PLWH with previous virological failure. The key secondary objectives are i) to determine whether switching to DOR / DTG / 3TC leads to lower burden of DDI compared to continuing a booster-containing regimen, and ii) to assess changes in patient perception on treatment acceptability and satisfaction, as well as health-related quality of life after a switch to booster-free ART.

Qualitative sub-study:

Qualitative objectives will be met using semi-structured interviews. Thirty people (15 from the intervention arm, 15 from the control arm) will be interviewed twice, at week 0 and week 48. Additional 15 individuals from the observational cohort will be interviewed once. Interviews will take place following study visits and performed using semi-structured guides. The guide for the interviews at week 48 will be based on results from analyses of the interviews conducted at week 0.

Study Overview

• Status: Enrolling by invitation
• Conditions: HIV; Drug Resistance; Drug Drug Interaction
• Intervention / Treatment: Drug: DOR/DTG/3TC

Detailed Description

Life expectancy of persons living with HIV on antiretroviral therapy (ART) is increasing and drug-drug interactions (DDI) with co-medications are becoming a major concern. Individuals who previously experienced virological failure are at risk of DDI as they are generally treated with ritonavir- or cobicistat-boosted ART. The high potency as well as the favorable safety and pharmacokinetic profile of new antiretroviral drugs, including dolutegravir (DTG) and doravirine (DOR), support their evaluation as part of un-boosted therapy for individuals with a history of virological failure. In this adaptive trial within the Swiss HIV Cohort Study (SHCS) and partner clinics in the Netherlands, the investigators aim to evaluate the efficacy and acceptability of the booster-free regimen DOR/DTG/3TC for treatment-experienced individuals.

• Study Type: Interventional
• Enrollment (Estimated): 210
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marie Ballif, PhD; Phone Number: +41 (0)31 632 27 45; Email: marie.ballif@insel.ch
• Study Contact Backup: Name: Bernard Surial, MD; Phone Number: +41 (0)31 632 27 45; Email: bernard.surial@insel.ch

Study Locations

• Switzerland
  • Basel, Switzerland
    • University Hospital Basel
    • Principal Investigator: Marcel Stöckle, Dr. med.
  • Bern, Switzerland, 3010
    • Inselgruppe AG
    • Contact: Bernard Surial, MD; Email: bernard.surial@insel.ch
    • Contact: Gilles Wandeler, Prof; Phone Number: +41787758533; Email: gilles.wandeler@insel.ch
  • Geneva, Switzerland
    • University Hospital Geneva
    • Principal Investigator: Alexandra Calmy, Prof.
  • Lausanne, Switzerland
    • University of Lausanne Hospitals
    • Principal Investigator: Matthias Cavassini, Prof.
  • Lugano, Switzerland
    • Lugano Regional Hospital Lugano
    • Principal Investigator: Enos Bernasconi, Prof.
  • St. Gallen, Switzerland
    • Cantonal Hospital of St. Gallen
    • Principal Investigator: Patrick Schmid, Dr. med.
  • Zürich, Switzerland
    • University Hospital Zurich
    • Principal Investigator: Dominique Braun, PD Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Informed consent as documented by signature
• Registered in the SHCS or ATHENA cohort study
• Age ≥18 years
• Documented HIV-1 infection
• On ART including a pharmacological booster (ritonavir or cobicistat) and at least 2 drugs from classes other than NRTI (e.g. non-nucleoside reverse transcriptase inhibitor, integrase-inhibitor, protease inhibitor or entry inhibitor)
• History of ART change due to virological failure
• HIV-RNA <50 cp/mL at screening and for at least 24 weeks before screening, one blip with less than 200 cp/mL allowed

Exclusion criteria

• Creatinine clearance <30mL/min, calculated using the CKD-EPI formula
• Known hypersensitivity, allergy, or intolerance to DOR, DTG, or 3TC
• Presence of major drug resistance mutations against DTG or DOR. DTG (G118R, G140R, Q148H, Q148K, Q148R, R263K) or DOR (V106A, Y188L, F227C, F227L, M230L, Y318F) according to IAS-USA. Patients without available resistance testing should not be excluded if no resistance to DTG and/or DOR is assumed based on ART history.
• Concomitant use of drugs that decrease DTG or DOR blood concentrations
• Chronic hepatitis B infection, defined as a positive hepatitis B surface antigen (HBsAg) at the screening visit
• Women who are pregnant or breast-feeding. Women of childbearing potential (women who are not surgically sterilized / hysterectomised and / or post-menopausal for longer than 2 years must have a negative pregnancy test at screening).
• Participation in another ART intervention study within the 30 days preceding and during the present study.

Qualitative sub-study

The same inclusion and exclusion criteria as those listed above will be applied. Fifteen persons who were excluded from the trial based on the exclusion criteria above will be recruited for qualitative interviews. In addition to the criteria mentioned above, individuals who are not fluent in German or French will be excluded from the qualitative sub-study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Doravirine 100 mg (Pifeltro®) will be administered once daily in combination with co-formulated dolutegravir/lamivudine 50/300 mg (Dovato®) for a duration of 48 weeks.	Drug: DOR/DTG/3TC; Doravirine 100 mg (Pifeltro®) will be administered once daily in combination with co-formulated dolutegravir/lamivudine 50/300 mg (Dovato®) for a duration of 48 weeks.; Other Names: Doravirine (Pifeltro®) + Dolutegravir/Lamivudine (Dovato®)
No Intervention: Control; Participants randomized to the control arm will continue to take their fully suppressive ART at baseline. The following selection of treatment combinations could be encountered in the control group (among others): Once-daily co-formulated elvitegravir 150 mg, cobicistat 150 mg, tenofovir alafenamide 10 mg, emtricitabine 200 mg (Genvoya®) and darunavir 800 mg (e.g. Darunavir Mylan®); Once-daily co-formulated darunavir 800 mg, cobicistat 150 mg, tenofovir alafenamide 10 mg, emtricitabine 200 mg (Symtuza ®) and DTG 50 mg (Tivicay ®); Once-daily DTG 50 mg (Tivicay®), darunavir 800 mg (e.g. Darunavir Mylan®), and ritonavir 100 mg (Norvir®); Etravirine 200 mg twice daily (Intelence®), raltegravir 400 mg twice daily (Isentress®),darunavir 800 mg once daily (e.g. Darunvair Mylan®) and ritonavir 100 mg once daily (Norvir®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Loss of viral suppression	Difference in the proportion of individuals with an HIV-RNA ≥50 cp/mL at 48 weeks between the treatment arms.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in DDI score from week 0 to 48	Using the University of Liverpool Drug Database (https://www.hiv-druginteractions.org/), the prescribed ART and co-medications will be categorized as red flag (3 points) for severe DDIs when co-administration is contraindicated, amber flag (2 points) for potential clinically significant DDIs manageable by dose adjustment or clinical monitoring, yellow flag (1 point) for DDIs of weak clinical relevance with no need of a priori dosage adjustment or monitoring, and a green flag (0 points) for no interactions. Amber flag DDIs will be downgraded to 1 point if there is evidence that the DDI was managed correctly (i.e. DTG administered 2 hours before or 6 hours after taking divalent cations). The sum of all points at visit 6, week 48 will be compared to baseline.	Week 0 and 48
Patient report outcomes concerning changes in treatment satisfaction between baseline and 48 weeks, as determined using the HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).	The investigators will assess changes in treatment satisfaction between week 0 and 48 using the validated HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).	Week 0 to 48
Proportion of patients experiencing confirmed virological failure	Proportion of patients experiencing confirmed virological failure, defined as 2 consecutive plasma HIV viral loads ≥200 copies/mL	Week 48
Proportion of individuals detected with new drug resistance	Proportion of individuals experiencing impairment / loss of future drug options throughout the study period, defined as new detection of resistance-associated mutations against DOR, DTG, 3TC (intervention-arm) or against the components of the ART regimen that the virus was considered to be sensitive to at randomization (based on historic resistance testing or treatment history; control-arm).	Week 0 to 48
Proportion of individuals with any moderate (orange flag) or severe (red flag) DDI	Proportion of individuals with any moderate (orange flag) or severe (red flag) DDI at any study visit between baseline and week 48, based on the results from the Liverpool drug interaction database (www.hiv-druginteractions.org).	Week 0 to 48
Proportion of patients with DDI leading to suboptimal management of comorbidities	Proportion of patients with DDI leading to suboptimal management of comorbidities between baseline and week 48, as reported by the cohort physician.	Week 0 and 48
Patient report outcomes concerning differences in quality of life between both groups at week 48 assessed by the World Health Organization Quality-of-Life- HIV Bref (WHOQOL-HIV BREF) questionnaire	Differences in quality of life between both groups at week 48, assessed using the World Health Organization Quality-of-Life- HIV Bref (WHOQOL-HIV BREF) questionnaire	Week 48
Patient report outcomes concerning differences in treatment satisfaction between both groups assessed by HIV Treatment Satisfaction Questionnaires	The investigators will assess the differences in treatment satisfaction between both groups at week 48, as determined using the validated HIV Treatment Satisfaction Questionnaires HIVTSQ.	Week 48
Proportion of individuals reporting depression assessed by Patient Health Questionnaire-9	Depression will be assessed at baseline and week 48, assessed using the Patient Health Questionnaire-9 (PHQ-9)	Week 0 and 48
Changes in intact proviral HIV-DNA levels	Changes in intact proviral HIV-DNA levels in peripheral blood mononuclear cells (PBMCs) between baseline and week 48. Stored PBMC samples will be used to determine HIV-DNA levels by a digital droplet PCR (ddPCR) assay using the RAINDANCE system.	Week 0 to 48
Proportion of individuals who develop a detectable HBV viral load	Proportion of individuals with a positive anti-HBc and negative anti-HBs ("anti-HBc alone") who develop a detectable HBV viral load (>50 IU/mL) at weeks 24 and 48.	Weeks 24 and 48
Cumulative cost of all ART drugs used	The 48-weeks cumulative cost of the received ART regimen will be calculated using prices published by the Federal Office of Public Health (https://www.spezialitaetenliste.ch/ShowPreparations.aspx).	Week 0 to 48
Perception of the trial and/or of HIV-related research in general assessed by qualitative interviews in a subset of approximately 30 trial participants	Perception of the trial and/or of HIV-related research in general.	Week 0 and 48
Acceptability conditions of participation in the trial assessed by qualitative interviews in a subset of approximately 30 trial participants	Acceptability conditions, understood as all barriers and facilitators to be involved in a trial.	Week 0 and 48
Needs regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants	Needs regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.	Week 0 and 48
Expectations regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants	Expectations regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.	Week 0 and 48
Perspectives on how the participants' current and anticipated needs can be assessed by qualitative interviews in a subset of approximately 30 trial participants	Perspectives on how the participants' current and anticipated needs can be addressed by research.	Week 0 and 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CD4 cell count from baseline to week 48	The CD4 cell counts will be obtained at baseline and week 48.	Week 0 and 48
Change in metabolic variables (cholesterol)	Change in total cholesterol	Week 0 and 48
Change in metabolic variables (low density lipoprotein)	Change in low density lipoprotein-cholesterol	Week 0 and 48
Change in metabolic variables (high density lipoprotein)	Change in high density lipoprotein-cholesterol	Week 0 and 48
Change in metabolic variables (triglycerides)	Change in triglycerides	Week 0 and 48
Change in body weight	Change in body weight from baseline to week 48	Week 0 and 48
Change in BMI	Change in BMI from baseline to week 48	Week 0 and 48
Change in renal function, assessed by glomerular filtration rate	Changes in glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) from baseline to week 48	Week 0 and 48
Change in renal function, assessed by urine protein-to-creatinine ratio	Change in renal function (glomerular filtration rate) using the urine protein-to-creatinine ratio from baseline to week 48	Week 0 and 48
Proportion of patients with new drug-related CNS symptom(s) at week 4	Proportion of patients with new drug-related central nervous system (CNS) symptom(s) at the 4 week visit.	Week 4
Proportion of patients with new drug-related CNS symptom(s) reporting new drug-related CNS symptom(s) at any time point between baseline and week 48.	Occurrence of CNS Adverse Events (AEs) in patients new to DTG	Week 0 to 48
Proportion of patients with a Serious Adverse Event (SAE) at any time point	Proportion of patients with a SAE, graded using the Division of AIDS table for grading AEs at any time point.	Week 0 to 48

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: University of Bern; Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland
• Investigators: Principal Investigator: Gilles Wandeler, Prof, Inselspital, Bern, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2023
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: September 7, 2023
• First Posted (Actual): September 14, 2023

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Dolutegravir; Drug resistance; Drug-drug interaction; Doravirine
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir
• Other Study ID Numbers: B-free trial - Stage 1

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
• product manufactured in and exported from the U.S.: No