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Renal safety of tenofovir in HIV treatment-experienced patients
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Correspondence in AIDS: Volume 18(7) 30 April 2004 pp 1074-1076
Izzedine, Hassanea; Isnard-Bagnis, Corinnea; Hulot, Jean- Sébastienb; Vittecoq, Danielc; Cheng, Andrewd; Jais, Carmen Krefte; Launay-Vacher, Vincenta; Deray, Gilberta
Departments of aNephrology, and bClinical Pharmacology, Pitie-Salpêtrière Hospital, Paris, France; cDepartment of Infectious Diseases, Kremlin Bicêtre Hospital, Paris, France; dGilead Sciences, Foster City, CA, USA; and eAgence Francaise pour la Sécurite Sanitaire des Aliments et Produits de Santé (AFSSAPS), Saint-Denis, France (The French Health Products Safety Agency).
The safety of tenofovir disoproxil fumarate (TDF) was assessed in two double-blind, placebo-controlled studies. Furthermore, we retrospectively collected 19 cases of TDF-associated tubular dysfunction. The incidence of renal events was similar among the active TDF groups and the placebo group in the two double-blind, placebo-controlled studies. Proximal tubulopathy was diagnosed 6.89 ± 5.51 months after TDF therapy started. All abnormalities normalized within 4.7 ± 2.94 weeks after drug discontinuation.
The renal parameters are reported in antiretroviral treatment-experienced patients included in two randomized double-blind, placebo-controlled studies of tenofovir disoproxil fumarate (TDF) in the treatment of HIV-1 infection. Furthermore, we retrospectively collected and analysed 19 cases of TDF-associated tubular dysfunction.
In study 902, 189 patients were randomly assigned to receive TDF or placebo: group 1 received TDF 75 mg/day, group 2 received TDF 150 mg/day, group 3 received TDF 300 mg/day, and group 4 received placebo for 48 weeks.
The mean and median values for serum creatinine remained constant for the four groups over the treatment period. All abnormalities were grade 1 in severity (0.5 mg/dl change from baseline). Over 48 weeks, the incidence of grade 1 elevations of serum creatinine levels was 6, 4 and 2% for the 75, 150 and 300 mg TDF groups, respectively. No patient discontinued treatment as a result of serum creatinine level elevations.
There were no marked changes from baseline in the median phosphorus levels in the three TDF groups. At week 48, the incidence of grades 1 or 2 hypophosphataemia was similar to that seen at week 24 (17, 14 and 24%) for the 75, 150 and 300 mg TDF groups, respectively.
In study 903, 552 patients were blindly randomly assigned to receive TDF 300 mg/day (368) or placebo (184) with their existing regimen. Twenty-four weeks after randomization, patients receiving placebo were blindly crossed over to TDF 300 mg/day for the remainder of the 48-week study.
The mean values for serum creatinine remained constant over the treatment period and the incidence of elevation in serum creatinine levels was similar between the TDF (2%) and placebo (1%) groups. All abnormalities were grade 1 and remained in the normal range i.e. less than 1.5 mg/dl (133 mmol/l). No patients discontinued treatment as a result of serum creatinine level elevations.
There were no marked changes in the mean and median serum phosphorus levels over the treatment period in all groups. Furthermore, grades 1 or 2 hypophosphataemia occurred in 12 and 7% of TDF and placebo-treated patients, respectively (P > 0.05). No patients discontinued treatment as a result of hypophosphataemia.
Proteinuria assessed using the dipstick test was not significantly different in the four groups of study 902. In addition, the 3+ urine glucose frequency was similar in all groups (3%).
Over the past 2 years, we collected data on 19 patients with tubular dysfunction: 13 men and six women (mean age 42.8 ± 9.8 years, mean HIV infection duration 12.8 ± 4 years). Four patients for which creatinine clearance was determined at baseline had renal insufficiency (from 32 to 78 ml/min). Tubular dysfunction or renal failure (a rise in the serum creatinine level of > 25%) was diagnosed 6.89 ± 5.51 months after starting TDF. All abnormalities normalized within 4.7 ± 2.9 weeks after drug discontinuation. One patient experienced tubular dysfunction when TDF was reintroduced. Symptoms resolved within a week after TDF withdrawal. Nephrogenic diabetes insipidus occurred in three cases and renal failure occurred in 14 out of the 19 cases. The mean serum creatinine level before TDF was 0.88 ± 0.24 mg/dl and the mean creatinine level after the increase was 2.64 ± 2.08 mg/dl. The mean serum creatinine level after recovery was 1.26 ± 0.44 mg/dl. TDF was withdrawn in 13 of the 14 patients and renal function improved in all cases. No patient died. In five patients, all antiretroviral agents except TDF were reintroduced after a while, with no increase in the serum creatinine level. All patients had at least one proximal tubular dysfunction abnormality in which this parameter was studied as assessed with normoglycemic glycosuria (100%), mild proteinuria (100%), hypophosphoremia (100%), metabolic acidosis with normal anion gap (53%), or hypokalemia (53%). Hypouricemia and aminoaciduria, which were not routinely performed tests, were found in five and two patients, respectively. Three antiretroviral drugs were frequently combined with TDF: lamivudine (47%), lopinavir (59%), and ritonavir (53%). Lopinavir and ritonavir were combined in six patients (31.5%). Kidney biopsy was obtained from five out of 19 patients. Microscopic examination revealed severe acute tubular necrosis associated with marked interstitial fibro-oedema. The distal and proximal renal tubules were both affected, with confluent necrosis of the proximal tubule epithelium and a dramatic vacuolization of these cells with a fading of the brush border. Dystrophic cells with karyomegaly were noted mainly in the proximal tubules. No tubular crystals were observed, glomerular vessels were found to be normal, and an immunofluorescence study was negative.
Recently, two cases of Fanconi's syndrome were reported during treatment with TDF [1,2]. The withdrawal of TDF treatment was associated with a rapid improvement of renal function in one [1], and the serum creatinine level remained stable at approximately 200 mmol/l for 2 months in the second case [2]. Another report showed TDF-induced nephrotoxicity in a patient with HIV and stable chronic kidney disease [3]. Furthermore, two other abstracts have reported six cases of proximal dysfunction related to tenofovir therapy [4,5]. From our 19 cases, we suggest that normoglycemic glycosuria and hypophosphoremia seem to be an effective sign of tenofovir-induced proximal tubulopathy. These changes are usually mild to moderate in severity and can be accompanied by a decrease in serum potassium, bicarbonate, uric acid, and proteinuria.
In HIV patients, renal manifestations include renal insufficiency (6-10%) [6,7] and electrolyte and acid-base disorders [8]. We have shown that abnormal blood glucose and hypophosphoremia are observed in up to 25.3 and 17.6% of those patients [9]. In the placebo group, renal insufficiency, hypophosphoremia and proteinuria were observed in 1, 7 and 1%, respectively. Furthermore, Szczech et al. [10] showed that 32% of 2057 HIV-positive women had proteinuria on initial evaluation. Moreover, Gardner et al. [11] reported that at baseline 7.2% of HIV-positive women had proteinuria or elevated serum creatinine levels. Therefore, all renal abnormalities observed in those patients must be interpreted cautiously. We confirm that renal abnormalities are frequent in HIV patients regardless of the treatment.
We therefore suggest that in two randomized, double blind studies tenofovir has no nephrotoxicity, tenofovir nephrotoxicity seems to be rare (≈ 20 cases out of more than 100 000 patients treated) and is reversible, and risk factors may include combination with ritonavir and pre-existing renal insufficiency.
Acknowledgements
The authors would like to thank Drs Jacques Reynes, Jean-Michel Molina, Jérôme Rossert, Pierre Marie Girard, Frank Martinez, Dominique Salmon and Christophe Piketti for providing most of the case reports.References
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