TDF/boosted protease inhibitor combination associated with higher CKD risk

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The risk of chronic kidney disease (CKD) may be increased in patients living with HIV receiving tenofovir (TDF) with a ritonavir-boosted protease inhibitor compared to those who receive TDF with a non-nucleosidic reverse transcriptase inhibitor (NNRTI), according to research by the Dat’AIDS study group.

To investigate whether certain antiretroviral (ART) combinations were associated with a greater risk of CKD, study authors evaluated a large prospective cohort (N=6,301) which included HIV patients who had initiated their first ART regimen after January 1, 2004, had at least 1 serum creatinine measurement within 6 months pre-ART regimen (study entry), and had at least 2 measurements after study entry. A CKD event was defined as an eGFR <60mL/min/1.73m2 measured 3 months apart. The time to event was the time between ART initiation and the first eGFR <60mL/min/1.73m2.

The regimens were divided into 5 combinations: TDF + ritonavir-boosted protease inhibitor, TDF + NNRTI, a ritonavir-boosted protease inhibitor without TDF, an NNRTI without TDF, and any other combination with or without TDF.

CKD occurrence was seen in 3.4% of patients, corresponding to an incidence of 9.6 (95% CI: 8.3–10.9) cases per 1000 person-years. Of these, 41% had developed CKD while on their initial ART regimen with an incidence of 6.9 cases per 1000 person-years.
The data showed a higher risk of CKD associated with an initial regimen of TDF with a ritonavir-boosted protease inhibitor vs. TDF + NNRTI (hazard ratio [HR] 2.15, 95% CI: 1.3–3.6; P=0.004). The increased risk was seen considering both initial and current regimens. Findings from the undadjusted Cox model also showed a higher CKD risk in the TDF with a ritonavir-boosted protease inhibitor group (HR 3.14, 95% CI: 1.4–7.0) vs TDF + NNRTI.

Lead author Lise Cuzin at INSERM, Toulouse, France; Université de Toulouse III; CHU Toulouse and COREVIH Toulouse, added, “Our analysis revealed a clinician-driven switch away from TDF among persons experiencing a decline in renal function while receiving this drug.”

Abstract
Objective: We investigated whether patients receiving selected antiretroviral combinations had a higher risk of chronic kidney disease (CKD) using traditional regression modeling and a causal approach in a large prospective cohort.
Patients and methods: For the purpose of this study, we selected 6301 patients who (i) started their first antiretroviral regimen after 1st January 2004, (ii) had at least one serum creatinine measurement within 6 months before ART initiation (study entry), and (iii) had at least two measurements after study entry. Baseline eGFR was defined from the last serum creatinine measurement before study entry. All eGFR values were calculated using the Modification of Diet and Renal Disease (MDRD) equation. Both traditional Cox proportional hazards model and Cox marginal structural models were applied. Distinct coding for antiretroviral therapy exposure were investigated as well as double robust estimators.
Results: Overall we showed that patients receiving tenofovir (TDF) with a ritonavir boosted protease inhibitor (rbPI) exhibited a higher risk of CKD compared with patients who received TDF with a non-nucleosidic reverse transcriptase inhibitor (NNRTI). Such an increased risk was observed considering both initial and current regimens. Our analysis revealed a clinician-driven switch away from TDF among persons experiencing a decline in renal function while receiving this drug.
Conclusion: Our results show that combination of TDF and boosted protease inhibitor is associated with a higher CKD risk than TDF and a NNRTI.

Authors
Lise Cuzin, Pascal Pugliese, Clotilde Allavena, David Rey, Catherine Chirouze, Firouzé Bani-Sadr, André Cabié, Thomas Huleux, Isabelle Poizot-Martin, Laurent Cotte, Corinne Isnard Bagnis, Philippe Flandre

MPR material
PLOS One abstract


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