Plain English Summary
Background and study aims
As HIV multiplies in the body, the virus sometimes changes form (mutates). Some HIV mutations that develop while a person is taking HIV medicines can lead to drug-resistant strains of HIV. Once drug resistance develops, HIV medicines that previously controlled a person’s HIV are no longer effective. In other words, the HIV medicines can't prevent the drug-resistant HIV from multiplying. Drug resistance can cause HIV treatment to fail. The aim of this study is to find out whether a new integrase inhibitor-based drug regimen is as effective as a regimen containing a protease inhibitor in controlling the multiplication of HIV virus which harbours resistance.
Who can participate?
Patients aged 18 and over who are HIV-positive and on effective antiretroviral treatment containing a protease inhibitor. Patients must have evidence that the virus is resistant to antiretroviral therapy.
What does the study involve?
Participants are randomly allocated to either continue on their current protease inhibitor-based regimen or switch to an integrase inhibitor-based regimen (tenofovir alafenamide/emtricitabine/bictegravir (Biktarvy) single tablet regimen). Participants continue on their allocated treatment for 24 weeks. At this point, if there is no difference in the response to both the regimens, all those who had remained on their protease-inhibitor based regimen are then switched to the new treatment and all participants are followed up for a further 24 weeks. No one in this study takes dummy tablets. All participants are on active treatment throughout the study. There are a total of eight scheduled study visits during the 48 weeks of the study, with a 30-day post-study treatment follow up call or standard of care visit.
What are the possible benefits and risks of participating?
The possible benefits include reduced cardiovascular risk (reduced risk of heart attacks and strokes) with continued suppression of the amount of virus in the blood, lower likelihood of interactions with other medications, and reduced number of tablets taken for HIV. Information gained from this study could lead to change in how doctors use the medication. Blood tests may cause discomfort and may leave a temporary bruise. Every effort will be made to minimise this. Because the study involves additional visits to the clinic, the researchers can reimburse reasonable travel expenses for those extra visits. When switching from one antiviral regimen to another, there is a small risk that the virus will not be controlled with the new regimen, hence the virus could develop resistance to the medications. Furthermore, the new regimen could cause new side effects. Viral load and side effects will be frequently and carefully monitored during this study to minimise these risks
Where is the study run from?
1. Brighton and Sussex University Hospitals NHS Trust
2. Barts Health NHS Trust
3. Central and North West London NHS Trust
4. King's College Hospital NHS Foundation Trust
5. Chelsea and Westminster NHS Trust
6. Royal Free London NHS Foundation Trust
7. Guy's and St Thomas' NHS Foundation Trust
When is the study starting and how long is it expected to run for?
November 2018 to October 2021
Who is funding the study?
Gilead Sciences (USA)
Who is the main contact?
1. Ye To
y.to@bsms.ac.uk
2. Nicky Perry
n.perry@bsms.ac.uk
2. Dr Collins Iwuji
c.iwuji@bsms.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Ms Ye To
ORCID ID
Contact details
Brighton and Sussex University Hospitals NHS Trust
Room 204
Bevendean House
Village Way
Brighton
BN1 9PH
United Kingdom
+44 (0)1273 641437
y.to@bsms.ac.uk
Type
Scientific
Additional contact
Dr Collins Iwuji
ORCID ID
http://orcid.org/0000-0003-2045-1717
Contact details
Global Health & Infection Department
Brighton and Sussex Medical School
University of Sussex
Brighton
BN1 9RH
United Kingdom
+44 (0)7984878861
c.iwuji@bsms.ac.uk
Type
Scientific
Additional contact
Ms Nicky Perry
ORCID ID
Contact details
Brighton and Sussex University Hospitals NHS Trust
Room 204
Bevendean House
Village Way
Brighton
BN1 9PH
United Kingdom
+44 (0)1273 641469
n.perry@bsms.ac.uk
Additional identifiers
EudraCT number
2018-004732-30
ClinicalTrials.gov number
Nil known
Protocol/serial number
CPMS 42164, IRAS 257865
Study information
Scientific title
A Phase IV, randomised, open-label pilot study to evaluate switching from protease-inhibitor based regimen to bictegravir/emtricitabine/tenofovir alafenamide single tablet regimen in integrase inhibitor-naïve, virologically suppressed HIV-1 infected adults harbouring drug resistance mutations
Acronym
PIBIK
Study hypothesis
This is a phase IV, multicentre, open-label, randomised two-arm pilot study to assess the safety and efficacy of switching from boosted protease inhibitor regimen to B/F/TAF single-tablet regimen in integrase Inhibitor-naïve, virologically suppressed HIV-1infected adults harbouring drug resistance mutations.
Ethics approval
Approved 28/06/2019, London – Brighton & Sussex Research Ethics Committee (Health Research Authority, Ground Floor, Skipton House, 80 London Road, London SE1 6LH; Tel: +44 (0)20 797 22567; Email: NRESCommittee.SECoast-BrightonandSussex@nhs.net), ref: 19/LO/0905
Study design
Randomised; Interventional; Design type: Treatment, Drug
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Human immunodeficiency virus [HIV] disease
Intervention
HIV-positive individuals who meet the eligibility criteria for the trial will be identified by their doctor and informed about the study. They will be referred to the doctor in charge of the research in each site where they will be given more information about the study and be given the opportunity to study the patient information leaflet and ask questions. Only after that will patients be consented and recruited into the study.
HIV-positive individuals will be randomised to either continue on their current protease inhibitor-based regimen or switch to an integrase inhibitor-based regimen (tenofovir alafenamide/emtricitabine/bictegravir (Biktarvy) single-tablet regimen). Participants will know which arm they fall into after the randomisation and which treatment they are taking. Participants will continue on their allocated treatment for 24 weeks. At this point, if there is no difference in the response to both the regimens, all those who had remained on their protease-inhibitor based regimen will then be switched to the new treatment and all participants will be followed up for a further 24 weeks. The study will continue until each person enrolled in the study has been followed up for 48 weeks from the time they joined the study. This will occur at different times for those involved depending on when they joined the study. No one in this trial will be on dummy tablets. All participants will be on active treatment throughout the study. There will be a total of eight scheduled study visits during the 48 weeks duration of the trial.
Updated 15/01/2020:
There will be a total of eight scheduled study visits during the 48 weeks duration of the trial, with a 30-day post-study treatment follow up call or standard of care visit.
Intervention type
Drug
Phase
Phase IV
Drug names
Tenofovir alafenamide, emtricitabine, bictegravir
Primary outcome measure
Proportions of individuals with HIV RNA <50 copies/mL at 24 weeks will be estimated using pure virologic response (PVR). The percentage of participants with PVR for HIV-1 RNA cut-off at 50 copies/mL at Week 24 will be summarized. PVR will be assessed as follows:
1. On study treatment
2. No confirmed virologic rebound defined as:
2.1. HIV RNA ≥ 50 copies/mL on 2 consecutive visits
2.2. HIV-1 RNA ≥ 50 copies/mL during study followed by premature discontinuation
Discontinuation prior to week 24 for reasons other than virologic rebound (i.e. no data in window and last HIV RNA < 50 copies/mL) are considered PVR
Timepoint(s): End of the study
Secondary outcome measures
1. Proportion of patients with HIV RNA <50 copies/mL at week 48 using PVR
2. Proportion of patients with HIV-1 RNA <50 copies/mL at weeks 24 and 48 using PVR in those with any archived resistance detected in proviral DNA
3. Emergence of new resistance mutations measured by population sequencing in participants with two consecutive viral load >50 copies/mL 2-3 weeks apart
4. Safety and tolerability of B/F/TAF FDC in participants switching from bPI-based regimens measured using laboratory parameters and clinical assessments at 48 weeks
5. Patient-reported outcomes: sleep quality measured using the Pittsburgh Sleep Quality Index and bothersome symptoms measured using the HIV symptom distress scale at baseline, weeks 24 and 48
6. Serum lipid concentrations measured using blood samples at baseline, weeks 24 and 48
7. HBA1c measured using blood samples at baseline, weeks 24 and 48
8. Weight and BMI measured using weighing scale for weight and measuring tape for height at baseline, weeks 24 and 48
Overall trial start date
01/11/2018
Overall trial end date
31/10/2021
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current inclusion criteria as of 15/01/2020:
1. 18 years and above
2. On a bPI-based ART regimen with at least one documented HIV-1 RNA < 50 copies/mL within the previous 6 months and at screening
3. Eligible drug resistance mutations in historical genotype include at least one of the following:
3.1. M184V/I with or without any nucleoside analogue mutation (e.g. L74I/V, Y115F, K70E/G/Q/T/N/S)
3.2. M184V/I alone (maximum of 20 participants with isolated M184V mutation with or without NNRTI mutations)
3.3. Up to 2 TAMs (M41L, D67N, K70R, L210W, T215F/Y, or K219Q/E/N/R) with or without M184V/I
3.4. Any of the above with or without NNRTI mutations
4. No previous use of any approved or experimental integrase strand transfer inhibitor (INSTI)
5. No known INSTI mutations
6. Must have historical genotype
7. Estimated GFR > = 50 mL/min (Cockcroft-Gault formula)
8. Have the following laboratory values at screening within 30 days prior to baseline
8.1. Alkaline phosphatase < = 3.0 x upper limit of normal (ULN)
8.2. AST and ALT < = 5.0 x ULN
8.3. Hemoglobin > = 9.0 g/dL (if female) or > = 10.0 g/dL (if male)
9. Provides written, informed consent to participate
10. Is willing to comply with the protocol requirements
11. If female and of childbearing potential, is using effective birth control methods (as agreed by the investigator) and willing to continue practising these birth control measures during the trial and for at least 30 days after the end of the trial
12. If male, and sexually-active with female partners of childbearing potential, is using effective barrier contraception, and willing to continue using this during the trial and for at least 30 days after the end of the trial
Previous inclusion criteria:
1. 18 years and above
2. Any nadir CD4 count and baseline VL
3. On a bPI-based ART regimen with at least one documented HIV-1 RNA < 50 copies/mL within the previous 6 months and at screening
4. Eligible drug resistance mutations in historical genotype include the following:
4.1. M184V/I with or without any nucleoside analogue mutation (e.g. L74I/V, Y115F, K70E/G/Q/T/N/S)
4.2. M184V/I alone
4.3. Up to 2 TAMs (M41L, D67N, K70R, L210W, T215F/Y, or K219Q/E/N/R) with or without M184V/I
4.4. Any of the above with or without NNRTI mutations
5. No previous use of any approved or experimental integrase strand transfer inhibitor (INSTI)
6. No known INSTI mutations
7. Must have historical genotype
8. Estimated GFR > = 50 mL/min (Cockcroft-Gault formula)
9. Have the following laboratory values at screening within 30 days prior to baseline
9.1. Alkaline phosphatase < = 3.0 x upper limit of normal (ULN)
9.2. AST and ALT < = 5.0 x ULN
9.3. Hemoglobin > = 9.0 g/dL (if female) or > = 10.0 g/dL (if male)
10. Provides written, informed consent to participate
11. Is willing to comply with the protocol requirements
12. If female and of childbearing potential, is using effective birth control methods (as agreed by the investigator) and willing to continue practising these birth control measures during the trial and for at least 30 days after the end of the trial
13. If male, and sexually-active with female partners of childbearing potential, is using effective barrier contraception, and willing to continue using this during the trial and for at least 30 days after the end of the trial
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 100; UK Sample Size: 100
Participant exclusion criteria
Current exclusion criteria as of 15/01/2020:
1. Exclusion under drug resistance mutations include:
1.1. Presence of any of the following mutations: K65R/N/E
1.2. Presence of multidrug resistance mutations: T69ins, Q151M with or without A62V, V75I, F77L, F116Y
1.3. Three or more TAMs (M41L, D67N, K70R, L210W, T215F/Y, or K219Q/E/N/R)
2. Individuals experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, or variceal bleeding)
3. An opportunistic illness within the 30 days prior to screening
4. Active tuberculosis infection
5. Have been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening, or expected to receive these agents or systemic steroids during the study (e.g., corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
6. Current alcohol or substance use judged by the Investigator to potentially interfere with participants’ adherence to study procedure
7. A history of malignancy of less than 5 years or ongoing malignancy (including untreated carcinoma in-situ) other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Individuals with biopsy-confirmed cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 and are not anticipated to require systemic therapy during the study
8. Active, serious infections (other than HIV 1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 (except if the parenteral therapy is for syphilis infection)
9. Any other clinical condition or prior therapy that will, in the opinion of the investigator, make the participant ineligible
10. Any known allergies to the excipients of B/F/TAF FDC
11. Females who are pregnant (as confirmed by positive urine pregnancy test)
12. Females who are breastfeeding
13. Women of childbearing age not using any reliable form of contraception (e.g. intrauterine device/intrauterine system, long-acting contraceptive injection, in addition to barrier methods)
14. Acute hepatitis in the 30 days prior to study entry, anyone with HCV who is likely to need direct-acting antivirals in study
15. Any concomitant medications that cannot be administered with TAF (i.e. strong inducers of p-glycoprotein) or bictegravir (dofetilide, rifampins)
Previous exclusion criteria:
1. Exclusion under drug resistance mutations include:
1.1. Presence of any of the following mutations: K65R/N/E
1.2. Presence of multidrug resistance mutations: T69ins, Q151M with or without A62V, V75I, F77L, F116Y
1.3. Three or more TAMs (M41L, D67N, K70R, L210W, T215F/Y, or K219Q/E/N/R)
2. Individuals experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, or variceal bleeding)
3. An opportunistic illness within the 30 days prior to screening
4. Active tuberculosis infection
5. Have been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening, or expected to receive these agents or systemic steroids during the study (e.g., corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
6. Current alcohol or substance use judged by the Investigator to potentially interfere with subjects’ adherence to study procedure
7. A history of or ongoing malignancy (including untreated carcinoma in-situ) other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Individuals with biopsy-confirmed cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 and are not anticipated to require systemic therapy during the study
8. Active, serious infections (other than HIV 1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 (except if the parenteral therapy is for syphilis infection)
9. Any other clinical condition or prior therapy that will, in the opinion of the investigator, make the subject ineligible
10. Any known allergies to the excipients of B/F/TAF FDC
11. Females who are pregnant (as confirmed by positive urine pregnancy test)
12. Females who are breastfeeding
13. Women of childbearing age not using any reliable form of contraception (e.g. intrauterine device/intrauterine system, long-acting contraceptive injection, in addition to barrier methods)
14. Acute hepatitis in the 30 days prior to study entry, anyone with HCV who is likely to need direct-acting antivirals in study
15. Any concomitant medications that cannot be administered with TAF (i.e. strong inducers of p-glycoprotein) or bictegravir (dofetilide, rifampins)
Recruitment start date
16/09/2019
Recruitment end date
16/10/2020
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Brighton and Sussex University Hospitals NHS Trust
Royal Sussex County Hospital
Eastern Road
Brighton
BN2 5BE
United Kingdom
Trial participating centre
Barts Health NHS Trust
The Royal London Hospital
Whitechapel
London
E1 1BB
United Kingdom
Trial participating centre
Central and North West London NHS Trust
Capper Street
London
WC1E 6JB
United Kingdom
Trial participating centre
King's College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom
Trial participating centre
Chelsea and Westminster NHS Trust
369 Fulham Road
London
SW10 9NH
United Kingdom
Trial participating centre
Royal Free London NHS Foundation Trust
Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom
Trial participating centre
Guy's and St Thomas' NHS Foundation Trust
Trust Offices
Guy's Hospital
Great Maze Pond
London
SE1 9RT
United Kingdom
Sponsor information
Organisation
University of Sussex
Sponsor details
Research & Enterprise
Brighton
BN1 9RH
United Kingdom
+44 (0)1273 872748
researchsponsorship@sussex.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Industry
Funder name
Gilead Sciences
Alternative name(s)
Gilead, Gilead Sciences, Inc., Gilead Sciences Inc
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
United States of America
Results and Publications
Publication and dissemination plan
1. The researchers aim to publish the protocol in a peer-reviewed journal and a copy of the paper will be uploaded once available
2. The results will be disseminated in peer-reviewed scientific journals and conference presentations
IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
30/10/2022
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list
2020 protocol in https://pubmed.ncbi.nlm.nih.gov/32689975/ (added 22/07/2020)