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

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

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 Overview

• Status: Active, not recruiting
• Conditions: HIV-infected Patient Kidney Transplant Recipient
• Intervention / Treatment: Drug: Biktarvy Tab

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Créteil, France, 94010
    • Hôpital Henri Mondor
  • Nantes, France, 44093
    • Hôpital Hotel Dieu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
• Collaborators: LAMBERT ASSOUMOU/ UNITE 1136 INSERM; Sebastien GALLIEN/Henri Mondor University Hospital- Infectiology Department; THOMAS STEHL/ HENRI MONDOR HOSPITAL-Department of Nephrology

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2022
• Primary Completion (Estimated): July 1, 2023
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: August 3, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 6, 2021

Study Record Updates

• Last Update Posted (Actual): May 25, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: HIV+,,KIDNEY TRANSPLANT, BIKTARVY,cALCINEURIN? mTOR
• Other Study ID Numbers: IMEA 064

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No