AIDS_24(11)1667#1678_RCI1AL4152 - (Page 1669)

eGFR, CKD and antiretroviral drug use in HIV-positive patients Mocroft et al. 1669 the finalmodel.Cumulative exposurewas also categorized intwoalternativeways: neverexposed, less than12,12–24, 24–36 and more than 36 months exposure and never exposed, exposed and currently on drug and exposed and currently off drug. In addition to including the individual antiretroviral drugs, use of cART was included as a categorical variable as anycART(yes/no) or type of cART (none, nonprotease inhibitor containing cARTor protease inhibitor -containing cART; further classified as nonboosted or ritonavir boosted). The primary analyses were repeated using the MDRD [15] and improved MDRD formula [34]. An additional sensitivity analysis with greater specificity forCKDwas used; confirmed decline in eGFR to 60ml/min per 1.73m2 or less where baseline eGFR above 80ml/min per 1.73m2 (i.e. 25% decline) or confirmed 25% decline in eGFR when baseline eGFR of 60ml/min per 1.73m2 or less [International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), M. Ross, personal communication]. We performed additional analyses censoring patients at starting specific antiretroviral drugs such as tenofovir, atazanavir or a boosted-protease inhibitor-containing regimen. For example, censoring patients at initiation of starting a boosted-protease inhibitor-containing regimen allows investigation of the effect of, for example, tenofovir, when it is used without a boosted protease inhibitor. All statistical analyses were performed using SAS version 9.1 (Statistical Analysis Software, Cary, North Carolina, USA). Results Out of 11 752 patients in EuroSIDAwith follow-up after 1 January 2004, 2590were excluded because they had less than three serum creatinine measurements and an additional 2319 patients were excluded because they did not have bodyweight, height or bothmeasured in order to calculate eGFR using the Cockcroft–Gault formula. Patients excluded from the Cockcroft–Gault analysis because of missing information on weight, height or both were similar to those included in the primary analyses. Patients excluded due to having insufficient serum creatinine measurements were more likely to be men, be of white ethnic origin, infected with HIV through intravenous drug use, be coinfected with hepatitis C virus and be from Eastern Europe. They were also recruited to EuroSIDA later and were younger in age. Six thousand, eight hundred and forty-three patientswere included; the median number ofeGFRmeasurements per patient was nine [interquartile range (IQR) 6–12] with a median time of 3.7 months (IQR 2.8–5.6) between measurements, and a median of 3.0 eGFR measurements per patient year of follow-up (IQR 2.3–3.6). The median date of baseline was July 2004 (IQR May 2004–August 2005). There was very little correlation between time between consecutive eGFR measurements and eGFR values (correlation coefficient 0.040, P<0.0001), and the correlation was similar at low (60 ml/min per 1.73m2; correlation coefficient 0.043) or high eGFR (>60 ml/min per 1.73m2; correlation coefficient 0.030). Two hundred and twenty-five patients (3.3%) progressed to CKD during 21 482 person-years of follow-up (PYFU), median follow-up was 3.7 years (IQR 2.8– 5.7) giving an overall incidence of 1.05 per 100 PYFU [95% confidence interval (CI) 0.91–1.18]. At baseline, 278 patients (4.1%) had an eGFR of 60 ml/min per 1.73m2or less and 4132 patients (60.4%) had an eGFR of above 90 ml/min per 1.73m2. Out of the 225 patients, 203 (90.2%) progressed due to a confirmed decline in eGFR to 60 ml/min per 1.73m2 or less and 150 (73.9%) progressed from an eGFR above 70 ml/min per 1.73m2 to 60 ml/min per 1.73m2 or less. Only 27 patients with a baseline eGFR above 90 ml/min per 1.73m2 progressed to CKD. Characteristics of the patients are shown in Table 1, together with a description of the patients stratified by whether they had, at baseline, ever been exposed to tenofovir, indinavir, atazanavir or lopinavir/r. There was little variation in the number of eGFR measurements per year of exposure to different antiretroviral drugs. For example, there was a median of 3.1 eGFR measurements per year while patientswere treated with tenofovir (IQR 2.4–4.0) compared with 2.5 eGFR measurements per year for indinavir (IQR 2.0–3.3), 3.0 per year for atazanavir (IQR 2.3–4.0) and 2.9 per year for lopinavir/r (IQR 2.2–3.8). Figure 1 shows the Kaplan–Meier progression to CKD; at 24 months, 1.48% (95% CI 1.18–1.78) were estimated to have developed CKD rising to 2.97% (95% CI 2.51– 3.43%) at 36 months after baseline. The crude (unadjusted) incidence of CKD stratified by years of exposure for commonly used antiretroviral drugs are shown in Fig. 2(a and b); a strong increasing incidence of CKD with increasing cumulative exposure to tenofovir, indinavir, atazanavir and lopinavir/r can be seen, which was less evident for efavirenz, abacavir, zidovudine or stavudine, although the test for trend was statistically significant. After adjustment (Table 2), a diagnosis of a new AIDS-defining event was associated with an increased incidence of CKD, as was female sex, older age, developing diabetes, being hypertensive and being hepatitis C antibody positive. In contrast, patients with a higher eGFR at baselinewere less likely to developCKD, aswere patients with a higher HIV-RNAviral load. Each additional year of exposure to tenofovir was associated with a 16% increased incidence of CKD, lopinavir/r with an 8% increased incidence, indinavir with an 11% increased incidence and atazanavir with a 22% increased incidence (P<0.05 for all). When atazanvir and tenofovir were used at the same time, there was a 41% increased incidence of CKD per year of additional exposure [incidence rate ratio (IRR) 1.41, 95% CI 1.24–1.61,

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