Clinical trial NCT04993872: Pharmacokinetics of Calcineurin & mTOR Inhibitors in HIV-1 Infected Kidney Transplant Recipients After Switch to BIC/FTC/TAF
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: HIV-infected Patient Kidney Transplant Recipient
Keywords: HIV+,,KIDNEY TRANSPLANT, BIKTARVY,cALCINEURIN? mTOR
Lead sponsor: Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
Sponsor class: OTHER
Collaborators: name: INSERM UMR S 1136
name: Sebastien GALLIEN/Henri Mondor University Hospital- Infectiology Department
name: THOMAS STEHL/ HENRI MONDOR HOSPITAL-Department of Nephrology
First posted: 2021-08-06
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Change in calcineurin & mTOR inhibitors' blood concentrations after switch to B/F/TAF
timeFrame: Week 2
Secondary outcomes:
measure: •Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF
timeFrame: Baseline
measure: •Proportion in calcineurin & mTOR inhibitors' dose changes after switch to B/F/TAF
timeFrame: Week 2
measure: • Changes in plasma levels of calcineurin & mTOR inhibitors
timeFrame: Week 2,
measure: • Changes in plasma levels of calcineurin & mTOR inhibitors
timeFrame: Week 12,
measure: • Changes in plasma levels of calcineurin & mTOR inhibitors
timeFrame: Week 24,
measure: • Changes in plasma levels of calcineurin & mTOR inhibitors
timeFrame: Week 48
measure: • B/F/TAF plasma levels
timeFrame: Week 4
measure: • Change in mGFR (iohexol clearance)
timeFrame: Baseline,
measure: • Change in mGFR (iohexol clearance)
timeFrame: Week 48
measure: • Change in bone markers
timeFrame: Baseline,
measure: • Change in bone mineral density
timeFrame: Baseline,
measure: • Change in bone mineral density
timeFrame: Week 48
measure: • Change in bone markers
timeFrame: Week 48
measure: • Incidence of proximal tubulopathy
timeFrame: W48
measure: • Incidence of proximal tubulopathy
timeFrame: Baseline
measure: • Change in eGFR evaluated with plasma or serum Cystatin C
timeFrame: Baseline
measure: • Change in eGFR evaluated with plasma or serum Cystatin C
timeFrame: Week 48
measure: • graft Survival
timeFrame: Baseline to Week 48
measure: • Change in plasma metabolome
timeFrame: Baseline to Week 48
measure: • Incidence of Grade ≥3 adverse events up
timeFrame: baseline to Week48
measure: • Incidence of specific calcineurin inhibitors
timeFrame: Baseline to Week 48
measure: • Antiretroviral therapy changes during the follow-up through
timeFrame: Baseline to Week 48
measure: • Calcineurin & mTOR inhibitors' drug dose changes
timeFrame: Baseline to Week 48
measure: • Proportion of patients with plasma HIV RNA ≤ 50 cp/mL
timeFrame: Week 48
measure: • Change CD4 cell count, ratio CD4/CD8
timeFrame: Baseline
measure: • Change CD4 cell count, ratio CD4/CD8
timeFrame: Week 24
measure: • Change CD4 cell count, ratio CD4/CD8
timeFrame: Week 48
measure: • proportion of participants with virological failure
timeFrame: Baseline to Week 48
measure: • Change in GSS* after switch to B/F/TAF Genotypic Susceptibility Score (GSS) to B/F/TAF
timeFrame: baseline to Week 48
measure: • Adherence, HIV Treatment Satisfaction
timeFrame: Baseline,
measure: • Adherence, HIV Treatment Satisfaction
timeFrame: Week12,
measure: • Adherence, HIV Treatment Satisfaction
timeFrame: ,Week 24,
measure: • Adherence, HIV Treatment Satisfaction
timeFrame: Week36,
measure: • Adherence, HIV Treatment Satisfaction
timeFrame: Week48
Other outcomes:
Locations:
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Nantes
country: France
facility: Hopital Hotel Dieu
Study officials:
References: