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Changes in Renal Function in Patients Treated with Tenofovir DF vs Nucleoside Reverse Transcriptase Inhibitors
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Reported by Jules Levin
Below are two studies reported at the 11th Annual retrovirus Conference (Feb 8-11, 2004, San Francisco) addressing tenofovir and questions related to it's potential effect on renal (kidney) impairment. In the first study reported immediately below--Joel Gallant and colleagues at Johns Hopkins School of Medicine Medical reported results from a study examining if a reduction in creatinine clearance, which can be associated with kidney or renal problems, was associated with tenofovir. Although some patients experienced reduced creatinine clearance, the use of tenofovir was not associated with reduced creatinine clearance. The study authors summarized, further studies are needed to evaluate disease state and the concurrent use of nephrotoxic agents as predictors of creatinine clearance decline in this population. The second study from Marianne Harris (Vancouver, Canada) reports on studying if a test, pre-tenofovir glomerular filtration rate (GFR) may be used prospectively to identify patients at risk for TDF-related nephrotoxicity.; resultsreported below.
Tenofovir DF (TDF) is the first nucleotide analog reverse transcriptase inhibitor (NRTI) approved for treatment of HIV disease. TDF is renally excreted via a combination of glomerular filtration and active tubular secretion. Renal impairment (including acute renal failure and Fanconi syndrome) has been reported in association with TDF use. Although the majority of cases have been associated with underlying systemic or renal disease, some cases occurred in patients without any identified risk factor.
To determine the effect of TDF vs NRTI on creatinine clearance we conducted a prospective longitudinal study of 476 HIV-infected patients treated with HAART by the Johns Hopkins AIDS service with up to 1 year follow-up. 211 took TDF and 265 used an NRTI, both starting in 2001. We assessed change in calculated creatinine clearance (Cockcroft-Gault equation) at start of treatment compared to that at the end of the observation period. Statistical comparisons were performed using paired t-test (before-after), independent t-test (TDF vs NRTI), and multivariate general linear modeling to assess multiple risk factors for creatinine clearanceL change.
RESULTS
Median duration of follow-up was 204 days for TDF users and 289 days for NRTI users (p < 0.05). Median serum creatinine at start of treatment was 0.8 and 0.8 mg/dL for the TDF and NRTI groups, respectively, with a significant mean change over time of +0.1 and +0.1 (both p <0.05). Median creatinine clearance change was -15.2 and -12.8 (both p <0.01), and median percentage of creatinine clearance decline was 12.5% and 11.1% (both p <0.01). Factors associated with percentage creatinine clearance decline were higher HIV RNA (p = 0.03) and lower CD4 (p = 0.03) at start of treatment, diabetes (p=.04), and hypertension (p = 0.009). Adjusting for these variables in a multivariate analysis of creatinineclearance decline, TDF use, concurrent use of ddI with TDF, prior use of adefovir, age, sex, and injection drug use were not significant predictors of creatinine clearance decline.
Significant declines in creatinine clearance were seen in all HIV-infected patients studied, with no significant difference seen between groups. The use of TDF was not a significant predictor of creatinine clearance decline. Further studies are needed to evaluate disease state and the concurrent use of nephrotoxic agents as predictors of creatinine clearance decline in this population.
Use of Estimated Glomerular Filtration Rate to Predict Renal Toxicity in Patients Receiving Tenofovir DF M Harris*1, N Zalunardo2, S Bonner1, R Werb2, M Valyi1, and J S G Montaner11British Columbia Ctr. for Excellence in HIV/AIDS, Vancouver, Canada and 2St. Paul's Hosp., Vancouver, Canada
Tenofovir DF (TDF) is not recommended for patients with renal impairment, defined as creatinine (Cr) clearance <60 mL/min. Cr clearance is not routinely measured; hence serum Cr is commonly used. TDF-related nephrotoxicityhas occurred in patients who had normal Cr before starting TDF. Therefore, westudied whether pre-TDF glomerular filtration rate (GFR) (estimated without 24-hrurine collection) in pts with TDF-related nephrotoxicity differed from the GFR of patients who took TDF without developing nephrotoxicity.
TDF was prescribed through an expanded access program startingDecember 2001. The present analysis included HIV+ adults who had serum Cr in the normal range (40 to 120 mmol/L) before starting TDF and who developed TDF-related renal toxicity, defined as clinically significant Cr increases on TDF with no other evident etiology, which resolved when TDF was discontinued. For each case, 2 gender-matched controls were randomly selected who started TDF in the same month and who remained on TDF with normal serum Cr as of September 2003. GFR was estimated using the modified MDRD formula of Levey et al.: 186 x Cr (mg/dL)--1.154 x age-0.203 x 1.212 if black x 0.742 if female (normal range for GFR 100-120 mL/min). The effect of pre-TDF baseline serum Cr and GFR were compared using logistic regression adjusting for the TDF start date.
Twelve male patients stopped TDF after 5 to 18 months because their Cr level increased; 8/12 also had evidence of drug toxicity on renal biopsy. Mean baseline serum Cr in these 12 cases was 101 mmol/L (range 73 to 120). Despite normal Cr at baseline, all 12 cases had GFR below the normal range before starting TDF: mean 74 mL/min (range 58 to 98); 10/12 had GFR <80. The 24 male controls had mean baseline Cr of 76 mmol/L (range 54 to 96) and mean GFR 104 mL/min (range 80 to 152). Baseline GFR was <100 mL/min in 10/24 controls but <80 in none. Baseline Cr was higher in cases (p = 0.0035), though still within the normal range; the odds ratio (OR) for renal toxicity was 1.16 per mmol/L increase in Cr. Baseline GFR was lower in cases than in controls (p = 0.0084); OR for renal toxicity was 1.19 per mL/min decrease in GFR.
Among male patients with serum Cr in the normal range, those with a reduced GFR, particularly those with GFR <80 mL/min appear to be at risk ofdeveloping nephrotoxicity on TDF. Our results suggest that a calculated estimate of GFR may be used prospectively to identify patients at risk for TDF-related nephrotoxicity.
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