1950 CID 2009:49 (15 December) HIV/AIDS. Received 17 April 2009; accepted 31 July 2009; electronically published 13 November 2009.

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1 HIV/AIDS BRIEF REPORT Long-Term Evolution and Determinants of Renal Function in HIV-Infected Patients Who Began Receiving Combination Antiretroviral Therapy in , ANRS CO8 APROCO-COPILOTE Catherine Leport, 1 Vincent Bouteloup, 4 Jérôme Rossert, 2 Michel Garré, 5 Laura Iordache, 1 Pierre Dellamonica, 6 Serge Herson, 3 François Raffi, 7 and Geneviève Chêne 4 ; for the ANRS CO8-COPILOTE study group a 1 Université Paris-Diderot, Paris 7, UFR Medecine, AP-HP, site Bichat, 2 Université Paris-Descartes University, AP-HP, Hôpital Européen Georges Pompidou, and 3 Hôpital Pitié-Salpêtrière, Paris, 4 INSERM U897, Université Victor Segalen, ISPED, Bordeaux, 5 Hôpital La Cavale Blanche, Brest, 6 Hôpital L Archet, Nice, and 7 Hôtel-Dieu, Nantes, France Among 1121 patients (90% Caucasian) infected by the human immunodeficiency virus (HIV), the glomerular filtration rate increased (+0.72 ml/min/1.73m 2 /month) from treatment initiation to month 16 (the rate increase was lower among men and those with low body mass index, AIDS, or receipt of indinavir), then remained stable up to 7 years. Kidney function should be monitored in patients previously exposed to indinavir. An elevated plasma creatinine level is associated with higher mortality and severe AIDS-related morbidity in human immunodeficiency virus (HIV)-infected patients, even in the era of combination antiretroviral therapy (cart) [1, 2]. Moreover, currently used antiretrovirals may be responsible for renal toxicity (eg, interstitial nephritis, tubular toxicity) [3 6]. The longterm evolution of renal function remains poorly described, as most studies of the relationship of antiretrovirals with renal dysfunction or kidney disease have focused on prevalence or have describing evolution over 3 years [7, 8]. We report renal Received 17 April 2009; accepted 31 July 2009; electronically published 13 November a Members of the study group are listed in the Appendix, which appears only in the online version of the journal. Reprints or correspondence: Dr Catherine Leport, Université Paris-Diderot, Paris 7, UFR Medecine, AP-HP, site Bichat, Laboratoire de Recherche en Pathologie Infectieuse, 16 rue Henri Huchard, Paris cedex 18, France (catherine.leport@univ-paris-diderot.fr). Clinical Infectious Diseases 2009; 49: by the Infectious Diseases Society of America. All rights reserved /2009/ $15.00 DOI: / function and its determinants over 7 years in a large cohort of HIV-infected patients who initiated cart. Patients and methods. The ANRS CO8 APROCO-COPI- LOTE cohort included 1281 patients who began cart with protease inhibitors from May 1997 through June 1999 in 47 French clinical centers. Standardized follow-up and data collection were performed at 1 month, 4 months, and every 4 months thereafter. Glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease formula [9], ignoring adjustment for race [10]. A mixed-effect linear model assessed for the following potential determinants of GFR slopes over time: age, sex, geographic origin (Caucasian vs origin from sub-saharan African countries or French overseas territories, ie, Guadeloupe, Guyana, Martinique, or Reunion Island), body mass index (BMI), diabetes, hypertension, prior AIDS diagnosis, hepatitis B and C virus serology status, specific antiretrovirals received (especially those reported to have a known renal toxicity, ie, tenofovir or indinavir), CD4 cell count, and plasma HIV RNA level. The time threshold (before and after 16 months) was used to maximize the fit of models to the data while remaining relevant, to estimate the impact of treatment initiation on GFR. Hypertension was defined as a systolic blood pressure 1140 mmhg and/or a diastolic blood pressure 190 mmhg occurring at least twice during follow-up. Diabetes was defined as a plasma glucose level 7 mmol/l (fasting) or 11.1 mmol/l (non-fasting) occurring at least twice during followup or receipt of specific treatment for diabetes. A Cox proportional hazards model was used to estimate the mortality rate according to different categories of GFR. All calculations were performed using SAS, version 9.1.3, service pack 2 (SAS Institute). Results. Among the 1281 patients enrolled in the cohort, 1121 had data available for all baseline characteristics. At enrollment, 77% were men, the median age was 37 years (interquartile range [IQR], years), 10% were of African/French overseas origin, 21% had a prior history of AIDS, the median creatinine level was 81 mmol/l (IQR, mmol/l), and the median GFR was 93 ml/min/1.73m 2 (IQR, ml/min/ 1.73m 2 ) (Table 1). After a median follow-up of 7.0 years (IQR, years) (ie, 6588 patient-years since protease inhibitor initiation), the median CD4 level increased from 273 cells/mm 3 (IQR, cells/mm 3 ) to 524 cells/mm 3 (IQR, cells/mm 3 ), whereas the median HIV RNA level decreased from 4.5 (IQR, log 10 copies/ml) to 1.7 log 10 copies/ml (IQR, CID 2009:49 (15 December) HIV/AIDS

2 Table 1. Kidney Function According to 3 Different Markers and Determinants of Glomerular Filtration Rate (GFR) at Protease Inhibitor (PI) Initiation in 1121 Human Immunodeficiency Virus (HIV)-Infected Patients Treated with Combination Antiretroviral Therapy (cart) for 17 years in the ANRS CO8-COPILOTE Cohort GFR, a ml/min/1.73m 2 Baseline characteristic Percentage of patients Median plasma creatinine level (IQR), mmol/l Median (IQR) P b categories (95% CI) c Adjusted difference between Overall (71 91) 93 (82 107) Sex Male (76 94) 95 (83 108)! (7.18 to 12.92) Female (62 76) 89 (80 102) Ref Age, years (70 88) 107 (97 114)! (14.65 to 28.45) (70 88) 98 (86 110) (8.40 to 16.37) (72 91) 92 (81 105) 8.63 (4.83 to 12.43) (71 96) 81 (72 95) Ref Geographic origin Sub-Saharan or French overseas (66 98) 91 (75 105) ( 4.67 to 3.35) Caucasian (71 90) 94 (83 107) Ref HIV transmission Injection drug use (66 85) 98 (87 113)! (3.12 to 8.59) Other modes (72 92) 93 (81 106) Ref Clinical stage AIDS (70 97) 92 (76 110) ( 1.15 to 5.25) No history of AIDS (71 90) 94 (83 106) Ref BMI, kg/m 2! (65 85) 100 (84 120)! (4.77 to 13.60) (73 91) 93 (82 106) 1.03 ( 2.23 to 4.29) (71 91) 92 (79 104) Ref CD4 count, cells/mm 3! (72 96) 91 (76 107) ( 7.12 to 1.77) (71 89) 95 (84 106) Ref Indinavir in the initial PI-based regimen Yes (73 93) 92 (79 105) ( 0.70 to 2.88) No (70 90) 94 (83 108) Ref NOTE. BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); CI, confidence interval; IQR, interquartile range; Ref, reference category. a Estimated with the Modification of Diet in Renal Disease formula. b Univariate mixed-effect linear model. c Multivariate mixed-effect linear model. log 10 copies/ml). The median BMI remained stable at 22 kg/ m 2 (IQR, kg/m 2 ); hypertension was reported in 18% of patients. The initial protease inhibitor received was most frequently indinavir (40%) or nelfinavir (29%). This regimen was modified in most of the patients; at 7 years, 13% were still receiving their initial protease inhibitor, 43% were receiving protease inhibitor based cart, 50% received a non protease inhibitor based regimen, and 7% had permanently interrupted ART. Overall, 532 patients were started on indinavir and received it for a median duration of 21 months (IQR, 9 42 months), whereas starting from 2001 onwards, 214 patients received tenofovir for a median duration of 20 months (IQR, 8 38 months). The median GFR was 93 ml/min/1.73m 2 (IQR, ml/ min/1.73m 2 ) at baseline, 97 ml/min/1.73m 2 (IQR, ) at 2 years, 96 ml/min/1.73m 2 (IQR, ) at 4 years, and 93 ml/min/1.73m 2 (IQR, ) at 6 years of follow-up. The change in GFR was best described by 2 slopes: ml/min/ 1.73m 2 /month (95% confidence interval, ) from baseline to month 16 and ml/min/1.73m 2 /month (95% confidence interval, 0.08 to 0.10) from month 16 onwards (Figure 1A). The proportion of patients with a GFR of!60 ml/min/ 1.73m 2 (3%) or ml/min/1.73m 2 (39% at baseline and 36% at 7 years of follow-up) remained stable over time. Overall, 5% of patients had at least 2 consecutive GFR measurements!60 ml/min/1.73m 2. The mortality rate was 4.1 per 100 person-years among patients with baseline GFR!60 ml/min/1.73m 2, 1.6% among HIV/AIDS CID 2009:49 (15 December) 1951

3 Figure 1. Evolution of glomerular filtration rate (GFR) over time in 997 human immunodeficiency virus (HIV)-infected patients treated with combination antiretroviral therapy (cart) for 17 years. Data are presented for all patients (A), according to receipt of indinavir (gray lines) or no receipt of indinavir (black lines) (B), or according to baseline CD4 count!200 cells/mm 3 (gray lines) or 200 cells/mm 3 (black lines) (C). MDRD, modification of diet renal disease expressed as ml/min/1.73m 2. Solid lines represent observed GFR measurements; dotted lines represent GFR estimates by the mixed-effect linear model. those with baseline GFR of ml/min/1.73m 2, and 1.8% among patients with GFR 90 ml/min/1.73m 2 ( P p.21, adjusted for baseline age, CD4 count, HIV RNA level, AIDS stage, and injection drug use). The baseline GFR was significantly higher in younger patients, injection drug users, and patients with low BMI and was lower in those with CD4 cell counts!200 cells/mm 3 (Table 1). The evolution of GFR over time did not differ between patients who initiated tenofovir, regardless of GFR (!90 vs 90 ml/ min/1.73m 2 /month), and those who never used tenofovir, and it did not differ for patients who received indinavir prior to tenofovir, compared with those who never received tenofovir (data not shown). In the multivariate analysis of GFR evolution over time (Table 2), male sex, AIDS stage, lower baseline BMI, and receipt of indinavir (Figure 1B) were associated with a poorer evolution of GFR during the first 16 months of treatment. Beyond 16 months, a poorer evolution of GFR was associated with African origin and baseline CD4 cell count 200 cells/mm 3 (Table 2 and Figure 1C) but not receipt of indinavir or tenofovir. Discussion. This is the longest follow-up report, to our knowledge, involving treated European HIV-infected patients 1952 CID 2009:49 (15 December) HIV/AIDS

4 Table 2. Determinants of Glomerular Filtration Rate (GFR) over Follow-up in 997 Human Immunodeficiency Virus Infected Patients Treated with Combination Antiretroviral Therapy for 17 Years, a Multivariate Mixed- Effect Linear Model Adjusted change of GFR a evolution (95% CI), ml/min/1.73m 2 /month Characteristic Baseline through month 16 Month 16 onwards Overall evolution 0.72 (0.40 to 1.03) 0.01 ( 0.08 to 0.10) Male vs female sex 0.23 ( 0.42 to 0.03) 0.01 ( 0.06 to 0.05) Age at PI initiation (vs age 50 years), years ( 0.30 to 0.64) 0.13 ( 0.01 to 0.26) ( 0.02 to 0.50) 0.01 ( 0.07 to 0.08) ( 0.26 to 0.24) 0.00 ( 0.07 to 0.07) Geographic origin sub-saharan or French overseas vs others 0.25 ( 0.52 to 0.02) 0.11 ( 0.19 to 0.04) AIDS clinical stage at PI initiation vs other stages 0.29 ( 0.50 to 0.07) 0.03 ( 0.03 to 0.08) BMI at PI initiation (vs 25), kg/m 2! ( 0.75 to 0.15) 0.05 ( 0.13 to 0.04) ( 0.26 to 0.17) 0.05 ( 0.10 to 0.01) CD4 cell count at PI initiation!200 vs 200 cells/mm ( 0.10 to 0.26) 0.06 (0.01 to 0.11) Receipt of tenofovir vs no tenofovir 0.01 ( 0.08 to 0.05) Receipt of indinavir vs no indinavir 0.42 ( 0.56 to 0.28) 0.01 ( 0.05 to 0.04) NOTE. BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); CI, confidence interval; PI, protease inhibitor. a Estimated with the Modification of Diet in Renal Disease formula. indicating stability of renal function over time. We show a strong association between age and renal function before initiation of cart and provide some evidence that patients treated with indinavir are at risk of developing impaired renal function, in addition to other traditional risk factors. We report a similar proportion (5%) of patients with renal dysfunction (defined as GFR!60 ml/min/1.73m 2 on 2 consecutive measurements) as in another European study [11]. Several studies have reported the beneficial effect of cart on renal disease, including non-hivan lesions [7, 12, 13]. The significant increase in GFR after cart initiation in our study is consistent with beneficial effects of the reduction of HIV replication on renal function. These beneficial changes suggest that renal function, when slightly altered, might then be improved by cart, as shown for HIV-associated nephropathy [14]. Conversely, the receipt of indinavir was associated with a reduced improvement in GFR. Though nephrolithiasis is one of the most frequently reported toxicities among patients treated with indinavir [15], reports of acute renal failure are rare [16]. However, prolonged use of indinavir may be associated with increases in serum creatinine level [16, 17], and improvement has been reported after dosage reduction [18]. Our longitudinal results corroborate those of a recent crosssectional study [11] reporting a deleterious effect of indinavir on renal function. In addition, the longitudinal design of our study allows reporting its early impact after cart initiation. Indinavir was the drug associated with the larger antiviral activity among available protease inhibitors in (ie, nelfinavir, ritonavir, and saquinavir). Even if this finding has less clinical relevance nowadays, it justifies specific attention to further deterioration of renal function in the large number of patients who have previously been exposed to indinavir. We report no significant change associated with the receipt of other antiretroviral agents, including tenofovir, even in the subgroup of patients who received indinavir prior to tenofovir. Moreover, the evolution of GFR in patients who initiated tenofovir with GFR!90 ml/min/1.73m 2 was not different from those who initiated tenofovir with GFR 90 ml/min/1.73m 2 and those who never used tenofovir, an observation which differs from that reported in the Swiss Cohort Study [19]. Conflicting results have been reported regarding the association between tenofovir use and nephrotoxicity, from no or little evidence [8, 20 22] to a clear association even after adequate adjustment for confounders [11, 23]. After 16 months and up to 7 years of cart, the moderate changes in GFR, although statistically significant, were consistent with those observed in the context of the natural evolution of GFR ( 0.5 ml/min/1.73m 2 per year) in an aging uninfected population [6]. Our long-term data further suggest that the favorable evolution of renal function with prolonged cart might primarily be related to long-term control of HIV replication [24]. HIV/AIDS CID 2009:49 (15 December) 1953

5 Among baseline HIV-related factors evaluated, injection drug use and a lower CD4 cell count were associated with a lower GFR, consistent with other studies [5, 11, 14]. Neither hypertension nor diabetes were associated with GFR evolution in our population, but we believe that close follow-up and case management of these patients may have led to early adequate treatment of these conditions. We did not study renal failure but rather the evolution of a renal biomarker, to have sufficient power for our analysis. Moreover, the effect of drugs is difficult to assess in an observational study, because it is not possible to attribute an observed change to drug exposure alone. Therefore, a lack of power or a selection bias might also explain our results regarding tenofovir; therefore, we cannot rule out its potential effect. In conclusion, renal function is remarkably stable over 7 years among cart-treated patients, and aging, as well as receipt of indinavir, is associated with early renal dysfunction. Clinicians should closely monitor renal function in cart-treated patients, especially in those who have been exposed to indinavir. Acknowledgments The authors thank the ANRS CO8 APROCO-COPILOTE Study Group. Financial support. The Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS). Potential conflicts of interest. All authors: no conflicts. References 1. Gardner LI, Holmberg SD, Williamson JM, et al. Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women. J Acquir Immune Defic Syndr 2003; 32: Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis 2004; 39: Gupta SK, Eustace JA, Winston JA, et al. 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