HIVPhase 4NCT02771054
Tenofovir Alafenamide Fumarate (TAF) Effect on Residual Intrathecal Immune Activation
A Phase 4 study testing TAF/FTC in people with HIV, run by Göteborg University at 1 site in Sweden.
Trial summary
Many HIV-infected individuals on effective antiretroviral therapy with suppressed HIV RNA levels in blood as well as in cerebrospinal fluid have signs of low-level intrathecal inflammation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV
- What is being tested?
- TAF/FTC
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteSweden
- Study dates
- 2 May 2016to 15 Jul 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Stable ART with TDF/FTC or ABC/3TC + 3rd agent (PI/r, NNRTI, or INI) >18 months
- Plasma HIV RNA < 50 copies/mL >12 months
- Lumbar puncture performed in the longitudinal CSF study (University of Gothenburg) between 6 and 18 months before study entry
Who cannot join
- Neurological symptoms or severe neurocognitive impairment
- Pre-treatment CNS opportunistic infection/ tumour or HIV-associated dementia
- Pregnancy
Trial locations and contacts
1 site in 1 country.
About this study
Many HIV-infected individuals on effective antiretroviral therapy with suppressed HIV RNA levels in blood as well as in cerebrospinal fluid have signs of low-level intrathecal inflammation. Our aim is to study if changing the nucleoside backbone in an antiretroviral regimen can decrease the residual intrathecal immune activation.
Read the detailed description
HIV infects the central nervous system (CNS) very early in the infectious course and establishes a chronic infection with markedly increased intrathecal immune activation. Modern antiretroviral treatment (ART) is effective not only to supress HIV in the blood and lymph system, but also in the CNS. After commencement of ART, markers of intrathecal immune activation such as cerebrospinal fluid (CSF) neopterin decreases markedly, but remains slightly increased in a substantial number of patients despite several years of receiving ART. CSF markers of immune activation correlates to markers of neuronal injury and the axonal marker neurofilament light protein (NFL) has been found to be slightly increased in asymptomatic patients compared to HIV-negative controls despite effective ART. This indicates a linkage between inflammation and neuronal injury, however, the long-term effect of low-grade immune activation within the CNS is not known.
CSF neopterin correlates also to levels of CSF HIV RNA in patients on ART when measured with ultrasensitive methods in the range 0.3-20 copies/mL highlighting the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury.
There are several indications that abacavir could act pro-inflammatory, a factor that might influence the proposed increased risk for coronary heart disease during abacavir treatment.
Tenofovir alafenamide fumarate (TAF) is a new prodrug for tenofovir and have some interesting differences compared to the currently used prodrug, tenofovir disoproxil fumarate (TDF). Both TDF and TAF require conversion to the active drug tenofovir diphosphate (DP). TDF is converted initially to tenofovir in the blood, then tenofovir is taken up into cells. In lymphocytes, macrophages, and some other cells, it is phosphorylated to the DP form. TAF, however, is largely delivered as TAF to lymphocytes and macrophages, then metabolized intracellularly to tenofovir and phosphorylated to the active tenofovir DP. Thus, plasma levels of tenofovir are much lower with TAF than with TDF, and tenofovir DP levels are much higher within lymphocytes and macrophages. This is of large interest since macrophages and microglia (a tissue macrophage) is the main target cells for HIV in the CNS.
A longitudinal study on HIV in CNS has been ongoing since more than 30 years in Gothenburg, Sweden. Subjects are followed with clinical follow up and annual lumbar punctures (LP), both before and during ART. Blood sampling is performed in parallel. The study protocol is approved by the Regional Ethical Review Board in Gothenburg and patients are included after written informed consent.
This is a pilot study and if we find interesting changes after treatment switch the idea is to continue with a larger study with design dependent on results and with enough power to demonstrate differences. However, the results from this study will be presented in a scientific publication irrespective of the outcome.
- No change in CSF viral load or CSF immune activation after switch.
- This outcome reassure a high effect in CNS also by TAF
- Decrease in CSF immune activation after switch from abacavir (ABC)/lamivudine (3TC)
- This would be a very interesting finding that in such case needs to be tested in a larger setting.
- Decrease in CSF viral load and/or CSF immune activation after switch in both groups
- This is an unlikely outcome but would imply that increased intracellular concentrations of tenofovir DP in macrophages and microglia could decrease an ongoing low-grade replication in the brain
- Increase in CSF immune activation after switch in one or two groups a. This is a highly unlikely outcome
- Conditions
- HIV
- Being tested
- TAF/FTC
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TAF/FTCDrug
Change of nucleoside backbone
| Study group | Role | What they receive |
|---|---|---|
| TAF/emtricitabine (FTC) | Experimental | All 20 patients will switch their nucleoside backbone, either ABC/3TC or TDF/FTC to TAF/FTC Receives: Drug: TAF/FTC |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction of CSF immune activation as measured by CSF neopterin
Measured: 12 months
Reduction of CSF immune activation as measured by CSF beta-2-microglobulin
Measured: 12 months
Reduction of CSF immune activation as measured by CSF immunoglobulin G index
Measured: 12 months
Secondary outcomes (1)
Reduction of CSF HIV RNA levels, quantified with a Roche Cobas Taqman version 2 after ultracentrifugation from 10 mL (detection limit 1-2 copies/mL).
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 May 2016 (estimated)
- Study start2 May 2016
- Primary completion15 Jul 2018
- Study completion15 Jul 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIVStudies of the same condition, open and under way.
- More trials run by Göteborg UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Göteborg University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02771054
- Sponsor's protocol ID
- 2015-004427-31
- Other IDs
- 2015
- Status last verified
- Nov 2018
- First submitted
- 27 Apr 2016
- Last updated
- 5 Nov 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Tenofovir Alafenamide Fumarate (TAF) Effect on Residual Intrathecal Immune Activation
- ClinicalTrials.gov ID
- NCT02771054
- Acronym / sponsor ID
- 2015-004427-31
- Conditions
- HIV
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Göteborg UniversityUniversity, hospital or other
- Study start
- 2 May 2016 (actual)
- Primary completion
- 15 Jul 2018 (actual)
- Study completion
- 15 Jul 2018 (actual)
- First posted
- 12 May 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Many HIV-infected individuals on effective antiretroviral therapy with suppressed HIV RNA levels in blood as well as in cerebrospinal fluid have signs of low-level intrathecal inflammation. Our aim is to study if changing the nucleoside backbone in an antiretroviral regimen can decrease the residual intrathecal immune activation.
Detailed description
HIV infects the central nervous system (CNS) very early in the infectious course and establishes a chronic infection with markedly increased intrathecal immune activation. Modern antiretroviral treatment (ART) is effective not only to supress HIV in the blood and lymph system, but also in the CNS. After commencement of ART, markers of intrathecal immune activation such as cerebrospinal fluid (CSF) neopterin decreases markedly, but remains slightly increased in a substantial number of patients despite several years of receiving ART. CSF markers of immune activation correlates to markers of neuronal injury and the axonal marker neurofilament light protein (NFL) has been found to be slightly increased in asymptomatic patients compared to HIV-negative controls despite effective ART. This indicates a linkage between inflammation and neuronal injury, however, the long-term effect of low-grade immune activation within the CNS is not known.
CSF neopterin correlates also to levels of CSF HIV RNA in patients on ART when measured with ultrasensitive methods in the range 0.3-20 copies/mL highlighting the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury.
There are several indications that abacavir could act pro-inflammatory, a factor that might influence the proposed increased risk for coronary heart disease during abacavir treatment.
Tenofovir alafenamide fumarate (TAF) is a new prodrug for tenofovir and have some interesting differences compared to the currently used prodrug, tenofovir disoproxil fumarate (TDF). Both TDF and TAF require conversion to the active drug tenofovir diphosphate (DP). TDF is converted initially to tenofovir in the blood, then tenofovir is taken up into cells. In lymphocytes, macrophages, and some other cells, it is phosphorylated to the DP form. TAF, however, is largely delivered as TAF to lymphocytes and macrophages, then metabolized intracellularly to tenofovir and phosphorylated to the active tenofovir DP. Thus, plasma levels of tenofovir are much lower with TAF than with TDF, and tenofovir DP levels are much higher within lymphocytes and macrophages. This is of large interest since macrophages and microglia (a tissue macrophage) is the main target cells for HIV in the CNS.
A longitudinal study on HIV in CNS has been ongoing since more than 30 years in Gothenburg, Sweden. Subjects are followed with clinical follow up and annual lumbar punctures (LP), both before and during ART. Blood sampling is performed in parallel. The study protocol is approved by the Regional Ethical Review Board in Gothenburg and patients are included after written informed consent.
This is a pilot study and if we find interesting changes after treatment switch the idea is to continue with a larger study with design dependent on results and with enough power to demonstrate differences. However, the results from this study will be presented in a scientific publication irrespective of the outcome.
- No change in CSF viral load or CSF immune activation after switch.
- This outcome reassure a high effect in CNS also by TAF
- Decrease in CSF immune activation after switch from abacavir (ABC)/lamivudine (3TC)
- This would be a very interesting finding that in such case needs to be tested in a larger setting.
- Decrease in CSF viral load and/or CSF immune activation after switch in both groups
- This is an unlikely outcome but would imply that increased intracellular concentrations of tenofovir DP in macrophages and microglia could decrease an ongoing low-grade replication in the brain
- Increase in CSF immune activation after switch in one or two groups a. This is a highly unlikely outcome
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| TAF/emtricitabine (FTC) | Experimental | Drug: TAF/FTCAll 20 patients will switch their nucleoside backbone, either ABC/3TC or TDF/FTC to TAF/FTC |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Stable ART with TDF/FTC or ABC/3TC + 3rd agent (PI/r, NNRTI, or INI) >18 months
- Plasma HIV RNA < 50 copies/mL >12 months
- Lumbar puncture performed in the longitudinal CSF study (University of Gothenburg) between 6 and 18 months before study entry
Key exclusion criteria (3 listed)
- Neurological symptoms or severe neurocognitive impairment
- Pre-treatment CNS opportunistic infection/ tumour or HIV-associated dementia
- Pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TAF/FTCChange of nucleoside backbone | Drug | TAF/emtricitabine (FTC) |
Primary outcome
Reduction of CSF immune activation as measured by CSF neopterin
Time frame: 12 months
Reduction of CSF immune activation as measured by CSF beta-2-microglobulin
Time frame: 12 months
Reduction of CSF immune activation as measured by CSF immunoglobulin G index
Time frame: 12 months
1 secondary outcome
Reduction of CSF HIV RNA levels, quantified with a Roche Cobas Taqman version 2 after ultracentrifugation from 10 mL (detection limit 1-2 copies/mL).
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2018.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing TAF/FTC in people with HIV, run by Göteborg University at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction of CSF immune activation as measured by CSF neopterin (time frame: 12 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2018; AzTrials last refreshed its copy on 8 Nov 2026.