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Kidney Risk & ARTs in Aquitaine Cohort
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
IAS: Antiretroviral drugs and incidence of chronic kidney disease, ANRS CO3 Aquitaine Cohort, France, 2004-2008 - (07/23/11)
Mark Mascolini
Taking tenofovir with a protease inhibitor (PI) more than tripled the risk of chronic kidney disease (CKD) in French Aquitaine cohort members with a median HIV duration of more than 7 years [1]. Women had a doubled risk of CKD, and people with a latest CD4 count under 200 had almost a quadrupled risk.
Tenofovir can cause impaired kidney function [2,3], a problem that ritonavir-boosted PIs may aggravate [4,5] because they can boost tenofovir concentrations [6]. To assess the impact of tenofovir, tenofovir plus PIs, and other factors on CKD risk, Aquitaine cohort investigators planned this study.
The analysis involved 2693 cohort members with an initial MDRD-estimated creatinine clearance above 60 mL/min/1.73m(2). Follow-up began in January 2004 and ended in December 2008. The investigators defined CKD as two consecutive creatinine clearance measurements below 60 mL/min/1.73m(2) at least 3 months apart. Statistical analysis to identify CKD risk factors included an array of initial or updated variables: CD4 count, viral load, exposure to antiretroviral therapy (ART), cumulative exposure to ART, high blood pressure, diabetes, hyperlipidemia, AIDS stage, and hepatitis B or C virus (HBV or HCV) coinfection. A second analysis also considered exposure to tenofovir with or without a ritonavir-boosted PI for more than 6 months.
Of the 2693 cohort members, 76% were men, 18% had a history of injection drug use, 4% injected drugs when follow-up began, and 21% had not taken ART at that point. When follow-up began, 66% of cohort members were younger than 45, 29% were 45 to 60, and 5% were older than 60. Initial creatinine clearance lay between 60 and 70 in 10% of the cohort, between 70 and 80 in 18.5%, between 80 and 90 in 22.5%, and above 90 in 49%.
When follow-up ended in December 2008, prevalence of diabetes was 5%, hyperlipidemia 55%, high blood pressure 17%, HBV coinfection 14%, and HCV infection 21%. At that point only 7.4% of cohort members had a CD4 count under 200, 15.1% had 200 to 350 CD4s, 25% had 350 to 500 CD4s, and 48.5% had more than 500 CD4s. Only 16.5% had a viral load above 500 copies in December 2008.
At the end of follow-up (a median of 3.4 years per person), CKD had developed in 86 people to yield an incidence of 10.1 cases per 100 person-years (95% confidence interval [CI] 8.3 to 12.7). Almost everyone, 95%, had started ART by the end of follow-up, including 35% who took tenofovir with a ritonavir-boosted PI for at least 6 months. Atazanavir/ritonavir proved the most-prescribed PI (41%), followed by lopinavir/ritonavir (35%), and fosamprenavir/ritonavir (11%). Median cumulative exposure to nucleos(t)ides at the end of follow-up was 7.4 years (interquartile range [IQR] 3.5 to 10.8), median exposure to tenofovir 1.9 years (IQR 0.9 to 3.5), and median exposure to PIs 3.6 years (IQR 1.7 to 6.8).
The multivariate model considering all variables except tenofovir with or without PIs identified eight independent predictors of CKD at the following risk ratios (RR) (and 95% confidence intervals):
--Female gender: RR 1.9 (1.1 to 3.1), P = 0.03
--Age 45 to 60 vs under 45: RR 2.0 (1.2 to 3.5), P = 0.006
--Age over 60 vs under 45: RR 3.2 (1.6 to 6.5), P = 0.006
--Diabetes: RR 2.2 (1.2 to 4.1), P = 0.03
--Hyperlipidemia: RR 2.1 (1.2 to 3.6), P = 0.08
--Initial creatinine clearance 60 to 70 vs over 90: RR 46.4 (13.9 to 154.9), P < 0.001
--Initial creatinine clearance 70 to 80 vs over 90: RR 18.7 (5.6 to 62.0), P < 0.001
--Latest CD4 count under 200 vs over 500: RR 3.8 (2.0 to 7.3), P = 0.02
Tenofovir use independently raised the risk of CKD with or without a ritonavir-boosted PI:
--Tenofovir ever vs never: RR 2.5 (1.5 to 4.1), P = 0.0002
--Tenofovir without a PI for more than 6 months vs never: RR 1.8 (1.0 to 3.3), P
= 0.0006
--Tenofovir with a PI for more than 6 months vs never: RR 3.5 (2.1 to 6.1), P = 0.0006
The Aquitaine investigators called for further study of the interaction between tenofovir and ritonavir-boosted PIs in cohorts big enough to determine whether the effect pertains to all PIs or only certain ones. "Meanwhile," they added, "use of tenofovir, mainly when co-administered with PIs, requires careful consideration" in people with other CKD risk factors.
References
1. Morlat P, Vivot A, Dauchy F, et al; Groupe d'Epidemiologie Clinique du SIDA en Aquitaine. Antiretroviral drugs and incidence of chronic kidney disease, ANRS CO3 Aquitaine cohort (2004-2008). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract WEPDB0104. http://pag.ias2011.org/EPosterHandler.axd?aid=3333.
2. Gallant JE, Moore RD. Renal function with use of a tenofovir-containing initial antiretroviral regimen. AIDS. 2009;23:1971-1975.
3. Mocroft A, Kirk O, Reiss P, et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS. 2010;24:1667-1668.
4. Fux CA, Simcock M, Wolbers M, et al. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study. Antivir Ther. 2007;12:1165-1173.
5. Goicoechea M, Liu S, Best B, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis. 2008;197:102-108.
6. Kearney BP, Mathias A, Mittan, A et al. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. J Acquir Immune Defic Syndr. 2006;43:278-283.
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