To study the renal safety when HIV patients with TDF related renal toxicity switch to TAF compared to the current practice of switching to ABC.
ID
Source
Brief title
Condition
- Immunodeficiency syndromes
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Recovery of renal dysfunction in the TAF arm versus the ABC arm at 48 weeks
after the switch from TDF to TAF or ABC using the time to the first eGFR within
75% of the eGFR at the time of TDF initiation.
Secondary outcome
* The between group differences (TAF vs ABC) with respect to the time to
recovery of renal dysfunction (eGFR improvement to within 75% of eGFR at TDF
initiation) at week 96, with adjustment for potentially important confounders.
* The mean eGFR at week 48 and 96 on ABC and TAF will be compared to week 0.
The slopes of eGFR-decline/increase between week 0, week 48 and 96 will be
compared between the ABC and TAF group.
* The median (IQR) of uPCR, uACR, uAPR, uB2MG/CR changes at week 48 and 96
compared to week 0 within the ABC and TAF group and difference in change
between both groups.
* Changes in the number of patients with at least 2 markers of PTD from week 0
to week 48 within the ABC and TAF group and difference in change of PTD markers
between both groups .
OTHER:
* HIV-RNA suppression rate <50 ABC versus TAF at week 48 and 96.
* Tolerability of TAF versus ABC, defined in terms of adverse events (%).
* Change in framingham risk-score, blood pressure, lipids and inflammation
parameters at week 0, 48 and 96 within the ABC and TAF group and comparison of
between group differences of these parameters.
Background summary
The majority of HIV-1 infected patients in resource rich countries take the
tenofovir prodrug tenofovir disoproxil fumarate (TDF) as part of their
combination antiretroviral therapy (cART) against HIV-1. Long-term exposure to
TDF is associated with an accelerated estimated glomerular filtration rate
(eGFR) decline and proximal tubular dysfunction (PTD) in a significant part of
these patients. The current practice in patients in which TDF related renal
toxicity becomes apparent is to substitute abacavir (ABC) for TDF. However, ABC
is contraindicated in patients with HLAB57*01 and has been associated with an
increased risk of cardiovascular disease. Recently, a new tenofovir prodrug,
tenofovir alafenamide (TAF) was developed by Gilead Sciences and is available
in a coformulation with emtricitabine (FTC). Due to the targeted delivery of
tenofovir inside the CD4 positive cell by this prodrug, only 25 mg TAF is
needed for the same antiviral effect observed in patients taking 250 mg of TDF.
In recently completed phase III studies in which patients with a normal kidney
function where included, the resulting lower tenofovir exposure in patients on
TAF was shown to prevent off-target renal and bone toxicity significantly in
comparison with patients taking TDF. However, whether an already established
TDF related renal toxicity in a HIV patient can be reversed after a switch to
TAF, remains to be shown.
Study objective
To study the renal safety when HIV patients with TDF related renal toxicity
switch to TAF compared to the current practice of switching to ABC.
Study design
To study the renal safety when HIV patients with TDF related renal toxicity
switch to TAF compared to the current practice of switching to ABC.
Intervention
HIV-1 infected adults, suppressed HIV-RNA <50c/mL on a TDF containing
antiretroviral regimen, with signs of TDF related renal toxicity as indicated
by an accelerated eGFR decline.
Study burden and risks
Burden: maximum of 4 extra visits for blood sampling (week 0, week 4, week 12,
week 36) and study drug accountability for all patients in the study. The other
visits at week 24, 48, 72 and 96 are the same as usual care, in which patients
are scheduled to visit their HIV physician at least every 24 weeks.
Risks: Risks associated with the study are the side effects of TAF or ABC. ABC
is EMA and FDA approved and recommended by international guidelines for use in
HIV patients. All patients will be tested for HLA-B57*01 which is associated
with a hypersensitivity reaction and patients who test positive will not be
randomized. ABC is safe, and the main side effects are gastro-intestinal. TAF
has been proven to be safe in 2 registration 96 weeks phase 3 randomized
clinical trials. Outside the context of this study, both switching to ABC or
TAF are advised by treatment guidelines as switch-strategy in patients with TDF
related renal toxicity.The virological properties of TAF and the low risk of
acquired resistance show that TAF is non-inferior to current practice (TDF) but
with lower (halved) eGFR decline over 48 weeks. The safety profile of TAF was
excellent in these trials and better than TDF. Nevertheless, because subjects
will be exposed to a small dose of the potential nephrotoxic agent, a delayed
recovery of eGFR or even a further decline of renal function might be possible.
The risk associated with standard blood sampling is very small (brusing,
syncope) and blood sampling is always done in the recumbent position to prevent
injury when syncope would occur). Patients will replace a mostly 1 pill cART
for a 2 pill cART (both in the ABC and in the TAF arm). However, this is also
often the current practice when these patients are treated outside the context
of a clinical trial.
Benefits: We cannot guarantee any specific benefits for the patients at this
time when they participate in the trial. However, both ABC and TAF are
anticipated to halt or ameliorate renal dysfunction If this indeed is the case,
the advantage will be that patients on TAF instead of ABC do not take ABC, a
drug that has been associated with in increased risk for myocardial infarction.
's Gravendijkwal 230
Rotterdam 3015CE
NL
's Gravendijkwal 230
Rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
* 18 years or older.
* Stable on TDF/FTC or TDF/3TC for ><=12 months (365 days) in combination with a third antiretroviral agent (NNRTI, INI, or PI) and with an unchanged 3th agent for at least 1 month .
* HIV-1 RNA <50 copies/mL for * 6 months.
* Confirmed/probable TDF-related accelerated eGFR decline
* Concomittantly used medication does not interfere with trial procedures (on investigators* discretion).
* Patient is negative for the HLA B5701 allele.
Exclusion criteria
* Likely other cause of non-TDF-related accelerated GFR decline:
* Diabetic patients
* Hypertensive patients (defined as the use of more than 2 antihypertensives or untreated systolic (>=160mmHg) or diastolic (>=95mmHg) hypertension) or hypertension with use of antihypertensives and with proteinuria at the screening visit..
* Nephrotic syndromes/nephrotic range proteinuria (uACR >300mg/mmol and uAPR * 0.4, or total 24hrs proteinuria >3.5g/24hr, or biopsy proven)
* Nephrotic syndromes including rapid progressive glomerulonephritis and tubular interstitial nephritis (defined as active urine sediment with erythrocyturia and leucocyturia and proteinuria with eGFR decline, with or without the presence of systemic disease, or biopsy proven).
* Obvious other renal toxic effects related to lifestyle or medication (e.g. creatin use) suspected by the investigators or biopsy proven.;* HLA-B5701 positivity.
* Active hepatitis C or B.
- Intermediate or high level resistance to ABC
- eGFR <30 ml/min
Symptomatic arterial disease e.g. a history of coronary artery disease, ischemic cerebrovascular accident or claudication intermittens in medical history.
* Any other disease or medical condition that, in the opinion of the investigators, would interfere with the safety of the participant or the conduct of the trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-005045-31-NL |
| ClinicalTrials.gov | NCT02957864 |
| CCMO | NL55668.078.16 |