Pharmacokinetics of Calcineurin & mTOR Inhibitors in HIV-1 Infected Kidney Transplant Recipients After Switch to BIC/FTC/TAF

Study Overview
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Brief Summary
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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.

Official Title
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Pharmacokinetics of Calcineurin & mTOR Inhibitors in HIV-1 Infected Kidney Transplant Recipients After Switch to BIC/FTC/TAF: a Pilot Study - KINETIK (KIdNEy Transplant bIKtarvy) IMEA 064

Conditions
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HIV-infected Patient Kidney Transplant Recipient

Intervention / Treatment
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* Drug: Biktarvy Tab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected patients > 18 years Kidney transplant recipient ≥ 3 months Receiving calcineurin and/or mTOR inhibitors without change in doses ≥ 4 weeks Plasma HIV RNA ≤ 50 cpml ≥ 6 months (1 blip permitted <200cp/ml) eGFR (CKD-EPI) ≥ 30 ml/mn/1.73m2 Written consent GSS to BIC/FTC/TAF GSS ≥ 2 stable antiretroviral regimen for at least 3 months Active contraception in potential child-bearing women Exclusion Criteria: Allergy or intolerance to one of the following drug or to any of excipients: FTC, TDF, INSTI HIV-2 or HIV-1/HIV-2 co-infection Patients with severe hepatic impairment (Child-Pugh Class C) Patient without health coverage Pregnancy and breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIC/FTC/TAF<br>Development phase 4: Biktarvy® | Drug: Biktarvy Tab<br>* Multicenter Pilot study aiming to assess the safe use of BIC/FTC/TAF in HIV-KTR, using a single-arm design.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in calcineurin & mTOR inhibitors' blood concentrations after switch to B/F/TAF | Evolution of blood concentration | Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| •Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF | PK of calcineurin and mTOR | Baseline | 
| •Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF | PK of calcineurin and mTOR | Week 2 | 
| • Changes in plasma levels of calcineurin & mTOR inhibitors | Plasma levels concentrations | Week 2, | 
| • Changes in plasma levels of calcineurin & mTOR inhibitors | Plasma levels concentrations | Week 12, | 
| • Changes in plasma levels of calcineurin & mTOR inhibitors | Plasma levels concentrations | Week 24, | 
| • Changes in plasma levels of calcineurin & mTOR inhibitors | Plasma levels concentrations | Week 48 | 
| • B/F/TAF plasma levels | B/F/TAF PK | Week 4 | 
| • Change in mGFR (iohexol clearance) | evolution of mGFR | Baseline, | 
| • Change in mGFR (iohexol clearance) | evolution of mGFR | Week 48 | 
| • Change in bone markers | bone markers and bone mineral density evolution | Baseline, | 
| • Change in bone mineral density | bone markers and bone mineral density evolution | Baseline, | 
| • Change in bone mineral density | bone markers and bone mineral density evolution | Week 48 | 
| • Change in bone markers | bone markers and bone mineral density evolution | Week 48 | 
| • Incidence of proximal tubulopathy | (hypouricemia, hypophosphatemia, low molecular weight proteinuria, orthoglycemic glycosuria) analysis | W48 | 
| • Incidence of proximal tubulopathy | (hypouricemia, hypophosphatemia, low molecular weight proteinuria, orthoglycemic glycosuria) analysis | Baseline | 
| • Change in eGFR evaluated with plasma or serum Cystatin C | evolution of eGFR | Baseline | 
| • Change in eGFR evaluated with plasma or serum Cystatin C | evolution of eGFR | Week 48 | 
| • graft Survival | defined as the necessity to return to dialysis, or death | 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 | Baseline to Week 48 | 
| • Incidence of Grade ≥3 adverse events up | adverse event≥3 reported | baseline to Week48 | 
| • Incidence of specific calcineurin inhibitors | histological renal damage performed (if graft biopsy ) | Baseline to Week 48 | 
| • Antiretroviral therapy changes during the follow-up through | Antiretroviral therapy changes | Baseline to Week 48 | 
| • Calcineurin & mTOR inhibitors' drug dose changes | Calcineurin & mTOR inhibitors' drug dose changes | Baseline to Week 48 | 
| • Proportion of patients with plasma HIV RNA ≤ 50 cp/mL | Proportion of patients with plasma HIV RNA ≤ 50 cp/mL | Week 48 | 
| • Change CD4 cell count, ratio CD4/CD8 | Immunology evolution | Baseline | 
| • Change CD4 cell count, ratio CD4/CD8 | Immunology evolution | Week 24 | 
| • Change CD4 cell count, ratio CD4/CD8 | Immunology evolution | 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 | Baseline to Week 48 | 
| • Change in GSS* after switch to B/F/TAF Genotypic Susceptibility Score (GSS) to B/F/TAF | GSS ≥ 2 | baseline to Week 48 | 
| • Adherence, HIV Treatment Satisfaction | adherence and satisfactory questionnaire | Baseline, | 
| • Adherence, HIV Treatment Satisfaction | adherence and satisfactory questionnaire | Week12, | 
| • Adherence, HIV Treatment Satisfaction | adherence and satisfactory questionnaire | ,Week 24, | 
| • Adherence, HIV Treatment Satisfaction | adherence and satisfactory questionnaire | Week36, | 
| • Adherence, HIV Treatment Satisfaction | adherence and satisfactory questionnaire | Week48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV+,,KIDNEY TRANSPLANT, BIKTARVY,cALCINEURIN? mTOR