Clinical trial NCT06037564: B-free Multistage Trial
Official title: Booster-free Antiretroviral Therapy for Persons Living With HIV and Multidrug Resistance: A Multicentre Multi-stage Randomized Trial
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: HIV
Drug Resistance
Drug Drug Interaction
Keywords: HIV
Doravirine
Dolutegravir
Drug resistance
Drug-drug interaction
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland
name: University of Bern
First posted: 2023-09-14
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-stage, randomized, multicenter, open-label non-inferiority trial with active control
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: Inclusion criteria

* Informed consent as documented by signature
* 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 (G118R, G140R, Q148H, Q148K, Q148R, R263K) or DOR (V106A, Y188L, F227C, F227L, M230L, Y318F) according to IAS-USA in individual cumulative resistance analyses. 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.

Primary outcomes:
measure: Loss of viral suppression
timeFrame: Week 48
Secondary outcomes:
measure: Changes in DDI score from week 0 to 48
timeFrame: Week 0 and 48
measure: Patient report outcomes concerning changes in treatment satisfaction between baseline and 48 weeks, as determined using the HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).
timeFrame: Week 0 to 48
measure: Proportion of patients experiencing confirmed virological failure
timeFrame: Week 48
measure: Proportion of individuals detected with new drug resistance
timeFrame: Week 0 to 48
measure: Proportion of individuals with any moderate (orange flag) or severe (red flag) DDI
timeFrame: Week 0 to 48
measure: Proportion of patients with DDI leading to suboptimal management of comorbidities
timeFrame: Week 0 and 48
measure: 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
timeFrame: Week 48
measure: Patient report outcomes concerning differences in treatment satisfaction between both groups assessed by HIV Treatment Satisfaction Questionnaires
timeFrame: Week 48
measure: Proportion of individuals reporting depression assessed by Patient Health Questionnaire-9
timeFrame: Week 0 and 48
measure: Changes in intact proviral HIV-DNA levels
timeFrame: Week 0 to 48
measure: Proportion of individuals who develop a detectable HBV viral load
timeFrame: Weeks 24 and 48
measure: Cumulative cost of all ART drugs used
timeFrame: Week 0 to 48
measure: Perception of the trial and/or of HIV-related research in general assessed by qualitative interviews in a subset of approximately 30 trial participants
timeFrame: Week 0 and 48
measure: Acceptability conditions of participation in the trial assessed by qualitative interviews in a subset of approximately 30 trial participants
timeFrame: Week 0 and 48
measure: Needs regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants
timeFrame: Week 0 and 48
measure: Expectations regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants
timeFrame: Week 0 and 48
measure: Perspectives on how the participants' current and anticipated needs can be assessed by qualitative interviews in a subset of approximately 30 trial participants
timeFrame: Week 0 and 48
Other outcomes:
measure: Change in CD4 cell count from baseline to week 48
timeFrame: Week 0 and 48
measure: Change in metabolic variables (cholesterol)
timeFrame: Week 0 and 48
measure: Change in metabolic variables (low density lipoprotein)
timeFrame: Week 0 and 48
measure: Change in metabolic variables (high density lipoprotein)
timeFrame: Week 0 and 48
measure: Change in metabolic variables (triglycerides)
timeFrame: Week 0 and 48
measure: Change in body weight
timeFrame: Week 0 and 48
measure: Change in BMI
timeFrame: Week 0 and 48
measure: Change in renal function, assessed by glomerular filtration rate
timeFrame: Week 0 and 48
measure: Change in renal function, assessed by urine protein-to-creatinine ratio
timeFrame: Week 0 and 48
measure: Proportion of patients with new drug-related CNS symptom(s) at week 4
timeFrame: Week 4
measure: 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.
timeFrame: Week 0 to 48
measure: Proportion of patients with a Serious Adverse Event (SAE) at any time point
timeFrame: Week 0 to 48
Locations:
city: Aarau
country: Switzerland
facility: Cantonal Hospital Aarau
state: Aargau
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: Inselgruppe AG
city: Geneva
country: Switzerland
facility: University Hospital Geneva
city: Lausanne
country: Switzerland
facility: University of Lausanne Hospitals
city: Lugano
country: Switzerland
facility: Lugano Regional Hospital Lugano
city: St. Gallen
country: Switzerland
facility: Cantonal Hospital of St. Gallen
city: Zürich
country: Switzerland
facility: University Hospital Zürich
Study officials:
affiliation: Inselspital, Bern, Switzerland
name: Gilles Wandeler, Prof
role: PRINCIPAL_INVESTIGATOR
References: