Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV (PLWH), with an estimated prevalence between 2.4 and 17%, leading to end-stage renal disease 3 to 6 fold more than non-HIV population. However kidney transplantation for PLWH has become the first-line therapy for end-stage renal disease, with an enhanced survival benefit compared to remaining on dialysis. Management of antiretroviral therapy (ART) in HIV-infected kidney transplant recipients (HIV-KTR) has historically been problematic because of the potential nephrotoxicity of some antiretroviral drugs and the interactions between calcineurin inhibitors, mTOR inhibitors, and ritonavir or cobicistat-boosted containing-ART. The use of tenofovir disoproxil fumarate (TDF), a widely recommended nucleotide analogue for the treatment of both HIV and HIV/hepatitis B virus (HBV) co-infection, is restricted in vulnerable kidney population as HIV-KTR due to its major potential toxicity consistent with tubular dysfunction and rarely with a progressive sustained decline in renal function. The optimal long-term ART regimen is not known in HIV-KTR, though it makes intuitive sense to avoid regimens containing TDF, given its potential nephrotoxicity. Nevertheless the potent virological efficacy of TDF both on HIV and HBV and its highest in-vitro barrier to resistance among the Nucleoside Reverse Transcriptase Inhibitors makes tenofovir use highly recommended or even essential in HIV/HBV co-infections. Tenofovir alafenamide (TAF) and bictegravir (BIC) are 2 novel antiretroviral drug available in HIV treatment in combination with emtricitabine (F) (B/F/TAF): \* TAF is a novel prodrug of tenofovir that may offer improved renal safety over TDF. TAF is more stable in plasma and is metabolized intracellularly by cathepsin A, an enzyme that is highly expressed in lymphoid tissues. Therefore, TAF can achieve higher intracellular levels of the active moiety tenofovir diphosphate, with lower levels of circulating tenofovir when compared with TDF. This more targeted treatment could potentially result in fewer renal and bone complications despite the same clinical efficacy as TDF. TAF was approved for use in PLWH with mild-moderate CKD (eGFR: 30-69 mL/min). The availability of TAF seems a potential addition to the antiretroviral armamentarium in HIV-KTR. \* BIC is a novel second-generation integrase strand transfer inhibitor (INSTI) has a high in-vitro barrier to resistance and in-vitro activity against most INSTI-resistant variants and has low potential for clinically meaningful drug-drug interactions. BIC has been recently approved by the FDA, in coformulated B/F/TAF for the treatment of HIV-1 infection in antiretroviral naïve subjects and in those with suppressed viremia. No data are available yet with TAF use in HIV-infected kidney transplant recipients as well as with BIC, especially about potential drug-to-drug interactions with immunosuppressive drugs such as calcineurin \& mTOR inhibitors. At last simplification to a single tablet regimen (STR) may offer a once-daily option for HIV-KTR who have multiple comorbidities, often requires complex regimens with a high pill burden.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
5
Multicenter Pilot study aiming to assess the safe use of BIC/FTC/TAF in HIV-KTR, using a single-arm design.
Hopital Henri Mondor
Créteil, France
Hopital Hotel Dieu
Nantes, France
Change in calcineurin & mTOR inhibitors' blood concentrations after switch to B/F/TAF
Evolution of blood concentration
Time frame: Week 2
•Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF
PK of calcineurin and mTOR
Time frame: Baseline
•Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF
PK of calcineurin and mTOR
Time frame: Week 2
• Changes in plasma levels of calcineurin & mTOR inhibitors
Plasma levels concentrations
Time frame: Week 2,
• Changes in plasma levels of calcineurin & mTOR inhibitors
Plasma levels concentrations
Time frame: Week 12,
• Changes in plasma levels of calcineurin & mTOR inhibitors
Plasma levels concentrations
Time frame: Week 24,
• Changes in plasma levels of calcineurin & mTOR inhibitors
Plasma levels concentrations
Time frame: Week 48
• B/F/TAF plasma levels
B/F/TAF PK
Time frame: Week 4
• Change in mGFR (iohexol clearance)
evolution of mGFR
Time frame: Baseline,
• Change in mGFR (iohexol clearance)
evolution of mGFR
Time frame: Week 48
• Change in bone markers
bone markers and bone mineral density evolution
Time frame: Baseline,
• Change in bone mineral density
bone markers and bone mineral density evolution
Time frame: Baseline,
• Change in bone mineral density
bone markers and bone mineral density evolution
Time frame: Week 48
• Change in bone markers
bone markers and bone mineral density evolution
Time frame: Week 48
• Incidence of proximal tubulopathy
(hypouricemia, hypophosphatemia, low molecular weight proteinuria, orthoglycemic glycosuria) analysis
Time frame: W48
• Incidence of proximal tubulopathy
(hypouricemia, hypophosphatemia, low molecular weight proteinuria, orthoglycemic glycosuria) analysis
Time frame: Baseline
• Change in eGFR evaluated with plasma or serum Cystatin C
evolution of eGFR
Time frame: Baseline
• Change in eGFR evaluated with plasma or serum Cystatin C
evolution of eGFR
Time frame: Week 48
• graft Survival
defined as the necessity to return to dialysis, or death
Time frame: Baseline to Week 48
• Change in plasma metabolome
(Indoxyl sulfate, indole-3-acetic acid, Hippuric acid, para-cresol sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) analysis
Time frame: Baseline to Week 48
• Incidence of Grade ≥3 adverse events up
adverse event≥3 reported
Time frame: baseline to Week48
• Incidence of specific calcineurin inhibitors
histological renal damage performed (if graft biopsy )
Time frame: Baseline to Week 48
• Antiretroviral therapy changes during the follow-up through
Antiretroviral therapy changes
Time frame: Baseline to Week 48
• Calcineurin & mTOR inhibitors' drug dose changes
Calcineurin \& mTOR inhibitors' drug dose changes
Time frame: Baseline to Week 48
• Proportion of patients with plasma HIV RNA ≤ 50 cp/mL
Proportion of patients with plasma HIV RNA ≤ 50 cp/mL
Time frame: Week 48
• Change CD4 cell count, ratio CD4/CD8
Immunology evolution
Time frame: Baseline
• Change CD4 cell count, ratio CD4/CD8
Immunology evolution
Time frame: Week 24
• Change CD4 cell count, ratio CD4/CD8
Immunology evolution
Time frame: Week 48
• proportion of participants with virological failure
defined as two consecutive HIV RNA VL\>50 copies/mL or a HIV RNA \>50 copies/mL followed by a study treatment discontinuation"
Time frame: Baseline to Week 48
• Change in GSS* after switch to B/F/TAF Genotypic Susceptibility Score (GSS) to B/F/TAF
GSS ≥ 2
Time frame: baseline to Week 48
• Adherence, HIV Treatment Satisfaction
adherence and satisfactory questionnaire
Time frame: Baseline,
• Adherence, HIV Treatment Satisfaction
adherence and satisfactory questionnaire
Time frame: Week12,
• Adherence, HIV Treatment Satisfaction
adherence and satisfactory questionnaire
Time frame: ,Week 24,
• Adherence, HIV Treatment Satisfaction
adherence and satisfactory questionnaire
Time frame: Week36,
• Adherence, HIV Treatment Satisfaction
adherence and satisfactory questionnaire
Time frame: Week48
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