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Enrolling by Invitation

NCT Number: NCT06037564

B-free Multistage 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.

Enrolling by Invitation

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Key information

Conditions

HIV Drug Drug Interaction Drug Resistance

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Cantonal Hospital Aarau, Aarau, Canton of Aargau, Switzerland

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

DOR/DTG/3TC

Drug

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®)

Primary outcomes

  1. Loss of viral suppression

    Time frame: Week 48

    Difference in the proportion of individuals with an HIV-RNA ≥50 cp/mL at 48 weeks between the treatment arms.

Secondary outcomes

  1. Changes in DDI score from week 0 to 48

    Time frame: Week 0 and 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.

  2. Patient report outcomes concerning changes in treatment satisfaction between baseline and 48 weeks, as determined using the HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).

    Time frame: Week 0 to 48

    The investigators will assess changes in treatment satisfaction between week 0 and 48 using the validated HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).

  3. Proportion of patients experiencing confirmed virological failure

    Time frame: Week 48

    Proportion of patients experiencing confirmed virological failure, defined as 2 consecutive plasma HIV viral loads ≥200 copies/mL

  4. Proportion of individuals detected with new drug resistance

    Time frame: Week 0 to 48

    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).

  5. Proportion of individuals with any moderate (orange flag) or severe (red flag) DDI

    Time frame: Week 0 to 48

    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).

  6. Proportion of patients with DDI leading to suboptimal management of comorbidities

    Time frame: Week 0 and 48

    Proportion of patients with DDI leading to suboptimal management of comorbidities between baseline and week 48, as reported by the cohort physician.

  7. 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

    Time frame: Week 48

    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

  8. Patient report outcomes concerning differences in treatment satisfaction between both groups assessed by HIV Treatment Satisfaction Questionnaires

    Time frame: Week 48

    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.

  9. Proportion of individuals reporting depression assessed by Patient Health Questionnaire-9

    Time frame: Week 0 and 48

    Depression will be assessed at baseline and week 48, assessed using the Patient Health Questionnaire-9 (PHQ-9)

  10. Changes in intact proviral HIV-DNA levels

    Time frame: Week 0 to 48

    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.

  11. Proportion of individuals who develop a detectable HBV viral load

    Time frame: Weeks 24 and 48

    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.

  12. Cumulative cost of all ART drugs used

    Time frame: Week 0 to 48

    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).

  13. Perception of the trial and/or of HIV-related research in general assessed by qualitative interviews in a subset of approximately 30 trial participants

    Time frame: Week 0 and 48

    Perception of the trial and/or of HIV-related research in general.

  14. Acceptability conditions of participation in the trial assessed by qualitative interviews in a subset of approximately 30 trial participants

    Time frame: Week 0 and 48

    Acceptability conditions, understood as all barriers and facilitators to be involved in a trial.

  15. Needs regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants

    Time frame: Week 0 and 48

    Needs regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.

  16. Expectations regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants

    Time frame: Week 0 and 48

    Expectations regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.

  17. Perspectives on how the participants' current and anticipated needs can be assessed by qualitative interviews in a subset of approximately 30 trial participants

    Time frame: Week 0 and 48

    Perspectives on how the participants' current and anticipated needs can be addressed by research.

Other outcomes

  1. Change in CD4 cell count from baseline to week 48

    Time frame: Week 0 and 48

    The CD4 cell counts will be obtained at baseline and week 48.

  2. Change in metabolic variables (cholesterol)

    Time frame: Week 0 and 48

    Change in total cholesterol

  3. Change in metabolic variables (low density lipoprotein)

    Time frame: Week 0 and 48

    Change in low density lipoprotein-cholesterol

  4. Change in metabolic variables (high density lipoprotein)

    Time frame: Week 0 and 48

    Change in high density lipoprotein-cholesterol

  5. Change in metabolic variables (triglycerides)

    Time frame: Week 0 and 48

    Change in triglycerides

  6. Change in body weight

    Time frame: Week 0 and 48

    Change in body weight from baseline to week 48

  7. Change in BMI

    Time frame: Week 0 and 48

    Change in BMI from baseline to week 48

  8. Change in renal function, assessed by glomerular filtration rate

    Time frame: Week 0 and 48

    Changes in glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) from baseline to week 48

  9. Change in renal function, assessed by urine protein-to-creatinine ratio

    Time frame: Week 0 and 48

    Change in renal function (glomerular filtration rate) using the urine protein-to-creatinine ratio from baseline to week 48

  10. Proportion of patients with new drug-related CNS symptom(s) at week 4

    Time frame: Week 4

    Proportion of patients with new drug-related central nervous system (CNS) symptom(s) at the 4 week visit.

  11. 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.

    Time frame: Week 0 to 48

    Occurrence of CNS Adverse Events (AEs) in patients new to DTG

  12. Proportion of patients with a Serious Adverse Event (SAE) at any time point

    Time frame: Week 0 to 48

    Proportion of patients with a SAE, graded using the Division of AIDS table for grading AEs at any time point.

Sponsors and collaborators

Lead sponsor

Insel Gruppe AG, University Hospital Bern

Other

Collaborators

  • Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland
  • University of Bern

Registry information

Official study title

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

Acronym: B-free

Important dates

Study start
2023
Primary completion
2026
Study completion
2027
First posted
Sep 14, 2023
Registry last updated
Dec 4, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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