xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06037564</url>
    </required_header>
    <id_info>
      <org_study_id>B-free trial - Stage 1</org_study_id>
      <nct_id>NCT06037564</nct_id>
    </id_info>
    <brief_title>B-free Multistage Trial</brief_title>
    <acronym>B-free</acronym>
    <official_title>Booster-free Antiretroviral Therapy for Persons Living With HIV and Multidrug Resistance: A Multicentre Multi-stage Randomized Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Insel Gruppe AG, University Hospital Bern</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of Bern</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Insel Gruppe AG, University Hospital Bern</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        The primary objective of the study is to evaluate the efficacy of a booster-free regimen&#xD;
        including DOR/DTG/3TC among HIV-suppressed PLWH with previous virological failure. The key&#xD;
        secondary objectives are i) to determine whether switching to DOR / DTG / 3TC leads to lower&#xD;
        burden of DDI compared to continuing a booster-containing regimen, and ii) to assess changes&#xD;
        in patient perception on treatment acceptability and satisfaction, as well as health-related&#xD;
        quality of life after a switch to booster-free ART.&#xD;
  &#xD;
        Qualitative sub-study:&#xD;
  &#xD;
        Qualitative objectives will be met using semi-structured interviews. Thirty people (15 from&#xD;
        the intervention arm, 15 from the control arm) will be interviewed twice, at week 0 and week&#xD;
        48. Additional 15 individuals from the observational cohort will be interviewed once.&#xD;
        Interviews will take place following study visits and performed using semi-structured guides.&#xD;
        The guide for the interviews at week 48 will be based on results from analyses of the&#xD;
        interviews conducted at week 0.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Life expectancy of persons living with HIV on antiretroviral therapy (ART) is increasing and&#xD;
        drug-drug interactions (DDI) with co-medications are becoming a major concern. Individuals&#xD;
        who previously experienced virological failure are at risk of DDI as they are generally&#xD;
        treated with ritonavir- or cobicistat-boosted ART. The high potency as well as the favorable&#xD;
        safety and pharmacokinetic profile of new antiretroviral drugs, including dolutegravir (DTG)&#xD;
        and doravirine (DOR), support their evaluation as part of un-boosted therapy for individuals&#xD;
        with a history of virological failure. In this adaptive trial within the Swiss HIV Cohort&#xD;
        Study (SHCS) and partner clinics in the Netherlands, the investigators aim to evaluate the&#xD;
        efficacy and acceptability of the booster-free regimen DOR/DTG/3TC for treatment-experienced&#xD;
        individuals.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 2023</start_date>
    <completion_date type="Anticipated">August 2027</completion_date>
    <primary_completion_date type="Anticipated">August 2025</primary_completion_date>
    <phase>Phase 4</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Multi-stage, randomized, multicenter, open-label non-inferiority trial with active control</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Single (Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Loss of viral suppression</measure>
      <time_frame>Week 48</time_frame>
      <description>Difference in the proportion of individuals with an HIV-RNA ≥50 cp/mL at 48 weeks between the treatment arms.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Changes in DDI score from week 0 to 48</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <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).</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>The investigators will assess changes in treatment satisfaction between week 0 and 48 using the validated HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of patients experiencing confirmed virological failure</measure>
      <time_frame>Week 48</time_frame>
      <description>Proportion of patients experiencing confirmed virological failure, defined as 2 consecutive plasma HIV viral loads ≥200 copies/mL</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of individuals detected with new drug resistance</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>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).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of individuals with any moderate (orange flag) or severe (red flag) DDI</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>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).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of patients with DDI leading to suboptimal management of comorbidities</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Proportion of patients with DDI leading to suboptimal management of comorbidities between baseline and week 48, as reported by the cohort physician.</description>
    </secondary_outcome>
    <secondary_outcome>
      <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</measure>
      <time_frame>Week 48</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Patient report outcomes concerning differences in treatment satisfaction between both groups assessed by HIV Treatment Satisfaction Questionnaires</measure>
      <time_frame>Week 48</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of individuals reporting depression assessed by Patient Health Questionnaire-9</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Depression will be assessed at baseline and week 48, assessed using the Patient Health Questionnaire-9 (PHQ-9)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in intact proviral HIV-DNA levels</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of individuals who develop a detectable HBV viral load</measure>
      <time_frame>Weeks 24 and 48</time_frame>
      <description>Proportion of individuals with a positive anti-HBc and negative anti-HBs (&quot;anti-HBc alone&quot;) who develop a detectable HBV viral load (&gt;50 IU/mL) at weeks 24 and 48.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cumulative cost of all ART drugs used</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>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).</description>
    </secondary_outcome>
    <secondary_outcome>
      <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</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Perception of the trial and/or of HIV-related research in general.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Acceptability conditions of participation in the trial assessed by qualitative interviews in a subset of approximately 30 trial participants</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Acceptability conditions, understood as all barriers and facilitators to be involved in a trial.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Needs regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Needs regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expectations regarding the booster-free regimen or regarding ART in general assessed by qualitative interviews in a subset of approximately 30 trial participants</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Expectations regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Perspectives on how the participants' current and anticipated needs can be assessed by qualitative interviews in a subset of approximately 30 trial participants</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Perspectives on how the participants' current and anticipated needs can be addressed by research.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Change in CD4 cell count from baseline to week 48</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>The CD4 cell counts will be obtained at baseline and week 48.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in metabolic variables (cholesterol)</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in total cholesterol</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in metabolic variables (low density lipoprotein)</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in low density lipoprotein-cholesterol</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in metabolic variables (high density lipoprotein)</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in high density lipoprotein-cholesterol</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in metabolic variables (triglycerides)</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in triglycerides</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in body weight</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in body weight from baseline to week 48</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in BMI</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in BMI from baseline to week 48</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in renal function, assessed by glomerular filtration rate</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Changes in glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) from baseline to week 48</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in renal function, assessed by urine protein-to-creatinine ratio</measure>
      <time_frame>Week 0 and 48</time_frame>
      <description>Change in renal function (glomerular filtration rate) using the urine protein-to-creatinine ratio from baseline to week 48</description>
    </other_outcome>
    <other_outcome>
      <measure>Proportion of patients with new drug-related CNS symptom(s) at week 4</measure>
      <time_frame>Week 4</time_frame>
      <description>Proportion of patients with new drug-related central nervous system (CNS) symptom(s) at the 4 week visit.</description>
    </other_outcome>
    <other_outcome>
      <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.</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>Occurrence of CNS Adverse Events (AEs) in patients new to DTG</description>
    </other_outcome>
    <other_outcome>
      <measure>Proportion of patients with a Serious Adverse Event (SAE) at any time point</measure>
      <time_frame>Week 0 to 48</time_frame>
      <description>Proportion of patients with a SAE, graded using the Division of AIDS table for grading AEs at any time point.</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">210</enrollment>
    <condition>HIV</condition>
    <condition>Drug Resistance</condition>
    <condition>Drug Drug Interaction</condition>
    <arm_group>
      <arm_group_label>Intervention</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>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):&#xD;
  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®)&#xD;
  Once-daily co-formulated darunavir 800 mg, cobicistat 150 mg, tenofovir alafenamide 10 mg, emtricitabine 200 mg (Symtuza ®) and DTG 50 mg (Tivicay ®)&#xD;
  Once-daily DTG 50 mg (Tivicay®), darunavir 800 mg (e.g. Darunavir Mylan®), and ritonavir 100 mg (Norvir®)&#xD;
  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®)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>DOR/DTG/3TC</intervention_name>
      <description>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.</description>
      <arm_group_label>Intervention</arm_group_label>
      <other_name>Doravirine (Pifeltro®) + Dolutegravir/Lamivudine (Dovato®)</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion criteria&#xD;
  &#xD;
            -  Informed consent as documented by signature&#xD;
  &#xD;
            -  Registered in the SHCS or ATHENA cohort study&#xD;
  &#xD;
            -  Age ≥18 years&#xD;
  &#xD;
            -  Documented HIV-1 infection&#xD;
  &#xD;
            -  On ART including a pharmacological booster (ritonavir or cobicistat) and at least 2&#xD;
               drugs from classes other than NRTI (e.g. non-nucleoside reverse transcriptase&#xD;
               inhibitor, integrase-inhibitor, protease inhibitor or entry inhibitor)&#xD;
  &#xD;
            -  History of ART change due to virological failure&#xD;
  &#xD;
            -  HIV-RNA &lt;50 cp/mL at screening and for at least 24 weeks before screening, one blip&#xD;
               with less than 200 cp/mL allowed&#xD;
  &#xD;
          Exclusion criteria&#xD;
  &#xD;
            -  Creatinine clearance &lt;30mL/min, calculated using the CKD-EPI formula&#xD;
  &#xD;
            -  Known hypersensitivity, allergy, or intolerance to DOR, DTG, or 3TC&#xD;
  &#xD;
            -  Presence of major drug resistance mutations against DTG or DOR. DTG (G118R, G140R,&#xD;
               Q148H, Q148K, Q148R, R263K) or DOR (V106A, Y188L, F227C, F227L, M230L, Y318F)&#xD;
               according to IAS-USA. Patients without available resistance testing should not be&#xD;
               excluded if no resistance to DTG and/or DOR is assumed based on ART history.&#xD;
  &#xD;
            -  Concomitant use of drugs that decrease DTG or DOR blood concentrations&#xD;
  &#xD;
            -  Chronic hepatitis B infection, defined as a positive hepatitis B surface antigen&#xD;
               (HBsAg) at the screening visit&#xD;
  &#xD;
            -  Women who are pregnant or breast-feeding. Women of childbearing potential (women who&#xD;
               are not surgically sterilized / hysterectomised and / or post-menopausal for longer&#xD;
               than 2 years must have a negative pregnancy test at screening).&#xD;
  &#xD;
            -  Participation in another ART intervention study within the 30 days preceding and&#xD;
               during the present study.&#xD;
  &#xD;
          Qualitative sub-study&#xD;
  &#xD;
          The same inclusion and exclusion criteria as those listed above will be applied. Fifteen&#xD;
          persons who were excluded from the trial based on the exclusion criteria above will be&#xD;
          recruited for qualitative interviews. In addition to the criteria mentioned above,&#xD;
          individuals who are not fluent in German or French will be excluded from the qualitative&#xD;
          sub-study.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Gilles Wandeler, Prof</last_name>
      <role>Principal Investigator</role>
      <affiliation>Inselspital, Bern, Switzerland</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Marie Ballif, PhD</last_name>
      <phone>+41 (0)31 632 27 45</phone>
      <email>marie.ballif@insel.ch</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Bernard Surial, MD</last_name>
      <phone>+41 (0)31 632 27 45</phone>
      <email>bernard.surial@insel.ch</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>University Hospital Basel</name>
        <address>
          <city>Basel</city>
          <country>Switzerland</country>
        </address>
      </facility>
      <investigator>
        <last_name>Marcel Stöckle, Dr. med.</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Inselgruppe AG</name>
        <address>
          <city>Bern</city>
          <zip>3010</zip>
          <country>Switzerland</country>
        </address>
      </facility>
      <contact>
        <last_name>Gilles Wandeler, Prof</last_name>
        <phone>+41787758533</phone>
        <email>gilles.wandeler@insel.ch</email>
      </contact>
      <contact_backup>
        <last_name>Bernard Surial, MD</last_name>
        <email>bernard.surial@insel.ch</email>
      </contact_backup>
    </location>
    <location>
      <facility>
        <name>University Hospital Geneva</name>
        <address>
          <city>Geneva</city>
          <country>Switzerland</country>
        </address>
      </facility>
      <investigator>
        <last_name>Alexandra Calmy, Prof.</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>University of Lausanne Hospitals</name>
        <address>
          <city>Lausanne</city>
          <country>Switzerland</country>
        </address>
      </facility>
      <investigator>
        <last_name>Matthias Cavassini, Prof.</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Lugano Regional Hospital Lugano</name>
        <address>
          <city>Lugano</city>
          <country>Switzerland</country>
        </address>
      </facility>
      <investigator>
        <last_name>Enos Bernasconi, Prof.</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Cantonal Hospital of St. Gallen</name>
        <address>
          <city>St. Gallen</city>
          <country>Switzerland</country>
        </address>
      </facility>
      <investigator>
        <last_name>Patrick Schmid, Dr. med.</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>University Hospital Zürich</name>
        <address>
          <city>Zürich</city>
          <country>Switzerland</country>
        </address>
      </facility>
      <investigator>
        <last_name>Dominique Braun, PD Dr. med.</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Switzerland</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>April 24, 2023</study_first_submitted>
    <study_first_submitted_qc>September 7, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 14, 2023</study_first_posted>
    <last_update_submitted>September 7, 2023</last_update_submitted>
    <last_update_submitted_qc>September 7, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>HIV</keyword>
    <keyword>Doravirine</keyword>
    <keyword>Dolutegravir</keyword>
    <keyword>Drug resistance</keyword>
    <keyword>Drug-drug interaction</keyword>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lamivudine</mesh_term>
      <mesh_term>Dolutegravir</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06037564
  org study id: B-free trial - Stage 1
  nct id: NCT06037564
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  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.
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Multi-stage, randomized, multicenter, open-label non-inferiority trial with active control
  primary purpose: Treatment
  masking: Single (Outcomes Assessor)
  measure: Loss of viral suppression
  time frame: Week 48
  description: Difference in the proportion of individuals with an HIV-RNA ≥50 cp/mL at 48 weeks between the treatment arms.
  measure: Changes in DDI score from week 0 to 48
  time frame: Week 0 and 48
  description: 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.
  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).
  time frame: Week 0 to 48
  description: The investigators will assess changes in treatment satisfaction between week 0 and 48 using the validated HIV Treatment Satisfaction Questionnaire HIVTSQc (change version).
  measure: Proportion of patients experiencing confirmed virological failure
  time frame: Week 48
  description: Proportion of patients experiencing confirmed virological failure, defined as 2 consecutive plasma HIV viral loads ≥200 copies/mL
  measure: Proportion of individuals detected with new drug resistance
  time frame: Week 0 to 48
  description: 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).
  measure: Proportion of individuals with any moderate (orange flag) or severe (red flag) DDI
  time frame: Week 0 to 48
  description: 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).
  measure: Proportion of patients with DDI leading to suboptimal management of comorbidities
  time frame: Week 0 and 48
  description: Proportion of patients with DDI leading to suboptimal management of comorbidities between baseline and week 48, as reported by the cohort physician.
  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
  time frame: Week 48
  description: 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
  measure: Patient report outcomes concerning differences in treatment satisfaction between both groups assessed by HIV Treatment Satisfaction Questionnaires
  time frame: Week 48
  description: 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.
  measure: Proportion of individuals reporting depression assessed by Patient Health Questionnaire-9
  time frame: Week 0 and 48
  description: Depression will be assessed at baseline and week 48, assessed using the Patient Health Questionnaire-9 (PHQ-9)
  measure: Changes in intact proviral HIV-DNA levels
  time frame: Week 0 to 48
  description: 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.
  measure: Proportion of individuals who develop a detectable HBV viral load
  time frame: Weeks 24 and 48
  description: 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.
  measure: Cumulative cost of all ART drugs used
  time frame: Week 0 to 48
  description: 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).
  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
  time frame: Week 0 and 48
  description: Perception of the trial and/or of HIV-related research in general.
  measure: 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
  description: Acceptability conditions, understood as all barriers and facilitators to be involved in a trial.
  measure: 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
  description: Needs regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.
  measure: 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
  description: Expectations regarding the booster-free regimen or regarding ART in general for participants included in the observational cohort.
  measure: 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
  description: Perspectives on how the participants' current and anticipated needs can be addressed by research.
  measure: Change in CD4 cell count from baseline to week 48
  time frame: Week 0 and 48
  description: The CD4 cell counts will be obtained at baseline and week 48.
  measure: Change in metabolic variables (cholesterol)
  time frame: Week 0 and 48
  description: Change in total cholesterol
  measure: Change in metabolic variables (low density lipoprotein)
  time frame: Week 0 and 48
  description: Change in low density lipoprotein-cholesterol
  measure: Change in metabolic variables (high density lipoprotein)
  time frame: Week 0 and 48
  description: Change in high density lipoprotein-cholesterol
  measure: Change in metabolic variables (triglycerides)
  time frame: Week 0 and 48
  description: Change in triglycerides
  measure: Change in body weight
  time frame: Week 0 and 48
  description: Change in body weight from baseline to week 48
  measure: Change in BMI
  time frame: Week 0 and 48
  description: Change in BMI from baseline to week 48
  measure: Change in renal function, assessed by glomerular filtration rate
  time frame: Week 0 and 48
  description: Changes in glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) from baseline to week 48
  measure: Change in renal function, assessed by urine protein-to-creatinine ratio
  time frame: Week 0 and 48
  description: Change in renal function (glomerular filtration rate) using the urine protein-to-creatinine ratio from baseline to week 48
  measure: Proportion of patients with new drug-related CNS symptom(s) at week 4
  time frame: Week 4
  description: Proportion of patients with new drug-related central nervous system (CNS) symptom(s) at the 4 week visit.
  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.
  time frame: Week 0 to 48
  description: Occurrence of CNS Adverse Events (AEs) in patients new to DTG
  measure: Proportion of patients with a Serious Adverse Event (SAE) at any time point
  time frame: Week 0 to 48
  description: Proportion of patients with a SAE, graded using the Division of AIDS table for grading AEs at any time point.
  arm group label: Intervention
  arm group type: Experimental
  description: 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.
  arm group label: Control
  arm group type: No Intervention
  description: 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®)
  intervention type: Drug
  intervention name: DOR/DTG/3TC
  description: 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.
  arm group label: Intervention
  other name: Doravirine (Pifeltro®) + Dolutegravir/Lamivudine (Dovato®)
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Gilles Wandeler, Prof
  role: Principal Investigator
  affiliation: Inselspital, Bern, Switzerland
  last name: Marie Ballif, PhD
  phone: +41 (0)31 632 27 45
  email: marie.ballif@insel.ch
  last name: Bernard Surial, MD
  phone: +41 (0)31 632 27 45
  email: bernard.surial@insel.ch
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  country: Switzerland
  responsible party type: Sponsor
  mesh term: Lamivudine
  mesh term: Dolutegravir
  sharing ipd: No