Pharmacokinetics of Calcineurin & mTOR Inhibitors in HIV-1 Infected Kidney Transplant Recipients After Switch to BIC/FTC/TAF
- Conditions
- HIV-infected Patient Kidney Transplant Recipient
- Interventions
- Registration Number
- NCT04993872
- Lead Sponsor
- Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 5
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description BIC/FTC/TAF Biktarvy Tab Development phase 4: Biktarvy®
- Primary Outcome Measures
Name Time Method Change in calcineurin & mTOR inhibitors' blood concentrations after switch to B/F/TAF Week 2 Evolution of blood concentration
- Secondary Outcome Measures
Name Time Method • Changes in plasma levels of calcineurin & mTOR inhibitors Week 48 Plasma levels concentrations
• Change in mGFR (iohexol clearance) Week 48 evolution of mGFR
• graft Survival Baseline to Week 48 defined as the necessity to return to dialysis, or death
• Incidence of Grade ≥3 adverse events up baseline to Week48 adverse event≥3 reported
• Incidence of specific calcineurin inhibitors Baseline to Week 48 histological renal damage performed (if graft biopsy )
• Calcineurin & mTOR inhibitors' drug dose changes Baseline to Week 48 Calcineurin \& mTOR inhibitors' drug dose changes
• Change CD4 cell count, ratio CD4/CD8 Week 48 Immunology evolution
• Change in GSS* after switch to B/F/TAF Genotypic Susceptibility Score (GSS) to B/F/TAF baseline to Week 48 GSS ≥ 2
• Adherence, HIV Treatment Satisfaction Week48 adherence and satisfactory questionnaire
•Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF Week 2 PK of calcineurin and mTOR
• B/F/TAF plasma levels Week 4 B/F/TAF PK
• Change in bone markers Week 48 bone markers and bone mineral density evolution
• Change in bone mineral density Week 48 bone markers and bone mineral density evolution
• Incidence of proximal tubulopathy Baseline (hypouricemia, hypophosphatemia, low molecular weight proteinuria, orthoglycemic glycosuria) analysis
• Change in eGFR evaluated with plasma or serum Cystatin C Week 48 evolution of eGFR
• Change in plasma metabolome Baseline to Week 48 (Indoxyl sulfate, indole-3-acetic acid, Hippuric acid, para-cresol sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) analysis
• Antiretroviral therapy changes during the follow-up through Baseline to Week 48 Antiretroviral therapy changes
• Proportion of patients with plasma HIV RNA ≤ 50 cp/mL Week 48 Proportion of patients with plasma HIV RNA ≤ 50 cp/mL
• proportion of participants with virological failure Baseline to Week 48 defined as two consecutive HIV RNA VL\>50 copies/mL or a HIV RNA \>50 copies/mL followed by a study treatment discontinuation"
Trial Locations
- Locations (2)
Hopital Henri Mondor
🇫🇷Créteil, France
Hopital Hotel Dieu
🇫🇷Nantes, France