Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naïve HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study

Hassane Izzedine1, Jean Sebastien Hulot2, Daniel Vittecoq3, Joel E. Gallant4, Schlomo Staszewski5, Vincent Launay-Vacher1, Andrew Cheng6, Gilbert Deray1 for the Study 903 Team

Departments of 1 Nephrology and 2 Clinical Pharmacology, Pitie-Salpêtrière Hospital, 3 Department of Infectious Diseases, Kremlin Bicêtre Hospital, Paris, France, 4 Johns Hopkins University School of Medicine, Baltimore, MD, 5 University Hospital, J. W. Goethe-Universität, Frankfurt, Germany and 6 Gilead Sciences, Foster City, CA, USA

Correspondence and offprint requests to: Hassane Izzedine, MD, Department of Nephrology, Pitié Salpêtrière Hospital, 47–83 Boulevard de l'Hôpital, 75013 Paris, France. Email: hassan.izzedine{at}psl.ap-hop-paris.fr



   Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Tenofovir disoproxil fumarate (TDF) was developed for the treatment of human immunodeficiency virus (HIV) infection. However, controlled data are sparse on the long-term renal tolerability of TDF at the currently approved daily dose of 300 mg in treatment-naive HIV-infected patients.

Methods. Over 144 weeks, this 600 patient, multicentre randomized, placebo-controlled, double-blind trial compared stavudine (301 patients) and TDF (299 patients), both administered in combination with lamivudine and efavirenz, in antiretroviral-naïve patients. TDF or placebo and stavudine or placebo were administered in an open-label fashion. All medications were taken orally. At screening, all patients had serum creatinines <1.5 mg/dl, calculated creatinine clearances ≥60 ml/min and a serum phosphorus ≥2.2 mg/dl.

Results. The incidences of grades 1 (≥0.5 mg/dl increase from baseline), 2 (2.1–3.0 mg/dl) and 3 (3.1–6.0 mg/dl) serum creatinine elevations at week 144 were 4, <1 and 0%, respectively, in the TDF group and 2, 0 and <1% in the stavudine control group (P = NS). There were no grade 4 (>6 mg/dl) serum creatinine elevations. At week 144, there was no change from baseline in the mean (0.83 mg/dl) serum creatinine in the TDF group compared with a 0.1 mg/dl decrease from baseline (0.83 mg/dl) in the stavudine control group. The incidences of grades 1 (2.0–2.2 mg/dl), 2 (1.5–1.9 mg/dl) and 3 (1.0–1.4 mg/dl) hypophosphataemia at week 144 were 4, 3 and <1%, respectively, in the TDF group and 4, 2 and <1% in the control group (P = NS). No patient experienced grade 4 (<1.0 mg/dl) hypophosphataemia. At week 144, the decrease ({Delta}) of mean serum phosphorus levels from baseline in both groups was similar ({Delta} 0.2 from 3.6 mg/dl for the TDF group, and 0.1 from 3.5 mg/dl for the stavudine control group). No patient developed Fanconi's syndrome or proximal renal tubular dysfunction during the study.

Conclusion. Through 144 weeks, TDF and stavudine, each administered in combination with efavirenz and lamivudine, had similar renal safety profiles in treatment-naive HIV-infected patients with normal renal function at baseline.

Keywords: long-term renal safety; tenofovir; tubulopathy



   Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Tenofovir disoproxil fumarate [(TDF)Viread®, Gilead Sciences) is an orally bioavailable ester prodrug of tenofovir, an acyclic nucleotide analogue with activity in vitro against retroviruses, including human immunodeficiency virus type 1 (HIV-1), HIV-2 and hepatitis B virus (HBV). Pre-clinical studies have shown that TDF is excreted unchanged in the urine of animals and that renal excretion is the primary route of elimination, by a combination of glomerular filtration and tubular secretion. Nephrotoxicity is the dose-limiting toxicity considered in the clinical use of acyclic nucleotide compounds, e.g. cidofovir and adefovir dipivoxil at high doses (60–120 mg/day), for the treatment of HIV disease. At exposures higher than those achieved with the 300 mg daily dose of TDF used in humans, some evidence of mild nephrotoxicity was observed in all three major animal species tested (dog, rat and monkey) [1]. Two double-blind studies recently reported that TDF has a renal safety profile similar to the control arm in treatment-experienced patients [2–4]; however, one of those reports [2] also described proximal renal tubular dysfunction in 19 cases. Since in those studies renal insufficiency was observed after as long as 18 months on TDF, and since other cases of renal impairment have been associated with TDF use [5–12], in this multicentre, randomized, double-blind trial we analysed the 144 week renal safety of TDF for the treatment of therapy-naive HIV-infected patients.



   Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study (Study 903) is a randomized, double-blind, parallel, placebo-controlled trial over 144 weeks, comparing a treatment regimen of TDF, lamivudine (3TC) and efavirenz (EFV) with a treatment regimen of stavudine (d4T), 3TC and EFV in antiretroviral-naïve patients. The design of this trial has been reported in detail previously [13]. In that study, statistically significant differences were observed between the two groups—with the TDF, 3TC, EFZ group comprising 299 subjects (mean age 35.5±8.63 years, 26% females, 64% whites, 21% blacks, HIV-1 RNA load 4.91±0.64, CD4 276±201) and the d4T, 3TC, EFZ group consisting of 301 (mean age 35.9±9.07 years, 25% females, 64% whites, 18% blacks, HIV-1 RNA load 4.91±0.61, CD4 282±200), as described in detail by Gallant et al. [13].

Main outcome measures for renal safety
The laboratory parameters monitored to assess renal safety included: serum creatinine, phosphorus, urea nitrogen, sodium, potassium, bicarbonate, uric acid and magnesium, as well as urinalysis to detect haematuria, proteinuria and glycosuria. Since weight and serum albumin levels were not available for the majority of the patients, the estimation of creatinine clearance could not be individually performed with either the Cockcroft and Gault formula or the Modification of Diet in Renal Disease formula.

Statistical analysis
All analyses were based on intent-to-treat. Changes over time in laboratory values were analysed using both a linear model and a repeated measures model, adjusting for baseline value. P-values were calculated based on a proportional hazards regression model. Fisher's exact test was used to compare proportions.



   Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Biological baseline characteristics were similar between groups (Table 1). The mean creatinine clearance of the two treatment groups, calculated using the Cockcroft–Gault equation, remained essentially unchanged from baseline (122 ml/min for the TDF arm and 125 ml/min for the d4T arm) at 144 weeks (+1.5 ml/min for the TDF arm and +6.7 ml/min for the d4T arm). The incidences of elevated serum creatinine and hypophosphataemia after 144 weeks of treatment are shown in Table 2. Mean serum creatinine values remained essentially unchanged from baseline (0.83 mg/dl for both arms) at 144 weeks in both groups (0.0 mg/dl for the TDF arm and –0.1 mg/dl for the d4T arm). In 18 patients [11 (4%) in the TDF group and seven (2%) in the d4T arm], we observed grade 1 elevations with respect to serum creatinine; two (<1%) patients (both in the TDF arm) had grade 2 serum elevations, and two (<1%) patients had grade 3 elevations (both in the d4T arm) (P = NS). No patient experienced a grade 4 creatinine elevation. In both patients in the TDF arm who developed them, grade 2 abnormalities occurred prior to week 48. Graded serum abnormalities largely resolved with continued dosing of the medication being studied. For example, of the graded abnormalities that were seen in 13 patients in the TDF arm, in four of them they were also seen on a second follow-up visit, but none were seen on a third visit. None of the serum creatinine abnormalities in the TDF arm led to permanent removal of patients from the study.


View this table:
[in this window]
[in a new window]
 
Table 1. Baseline biochemical characteristics of the cohort (n = 600) (mean±SD)

 

View this table:
[in this window]
[in a new window]
 
Table 2. Maximum toxicity grade reported along the 144 weeks of the study for serum creatinine and serum phosphorus [13]

 
In both groups, there were slight decreases (0.2 mg/dl in the TDF arm and 0.1 mg/dl in the d4T arm) at week 144 in mean serum phosphorus values from baseline (3.6 mg/dl for the TDF arm and 3.5 mg/dl for the d4T arm). Among the 299 and 301 patient in the TDF and control groups, the incidence of grade 1, 2 and 3 hypophosphataemia through 144 weeks was 4% (12 out of 296), 3% (nine out of 296) and <1% (one out of 296), respectively, in the TDF arm, and 4% (11 out of 296), 2% (six out of 296) and <1% (two out of 296) in the d4T arm (P = NS). No patient experienced grade 4 hypophosphataemia. The one grade 3 abnormality in the TDF arm occurred prior to week 48. Graded serum phosphorus abnormalities largely resolved with continued dosing of study medication. For example, of the graded abnormalities in the 22 patients in the TDF arm, one was seen in one patient on a second follow-up visit, but none were seen on a third visit. No patient in the TDF arm received treatment-emergent phosphate supplementation, and none of the serum phosphorus abnormalities led to the permanent removal of a patient from the study.

Grades 1–3 haematuria, proteinuria and glycosuria were found to occur equally in both groups (Table 3). No patients developed grade 4 dipstick abnormalities or nephrotic syndrome. No patient developed Fanconi's syndrome or proximal renal tubular dysfunction during the study.


View this table:
[in this window]
[in a new window]
 
Table 3. Dipstick abnormalities after 144 weeks of treatment of patients treated with tenofovir DF 300 mg daily dose and of active-controlled groups

 
There was also no evidence of renal toxicity related to TDF in individual adverse event reports. During the first 144 weeks (the double-blind portion) of the study, three cases of acute renal failure were reported, each of which occurred during the first 48 weeks of the study. Two cases of acute renal failure in the TDF arm occurred in patients with other risk factors for renal dysfunction, and the investigator felt both events to be unrelated to TDF. In one case, the patient had not taken TDF for 6 weeks, and was receiving cidofovir without probenecid at the time of renal failure. The other case involved a patient with acute alcohol intoxication who developed a compartment syndrome and severe rhabdomyolysis. One event requiring haemodialysis occurred in a patient taking d4T.

Other drugs that may have interacted with the pharmacokinetics of tenofovir (didanosine, ritonavir, lopinavir, etc.) were equally distributed between both groups.



   Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Nephrotoxicity is the dose-limiting toxicity associated with the clinical use of nucleotide analogue reverse transcriptase inhibitors, e.g. cidofovir and high dose adefovir dipivoxil (60–120 mg).

The addition of TDF to background antiretroviral regimens was not associated with nephrotoxicity at 24 weeks, when compared with placebo, in two randomized double-blind, placebo-controlled studies that included 186 (Study 902) and 550 (Study 907) HIV-infected patients with normal baseline renal functions (calculated creatinine clearance >60 ml/min, serum creatinine <1.5 mg/dl and serum phosphorus ≥2.2 mg/dl) [2–4]. However, 19 cases of tenofovir-associated proximal renal tubular dysfunction have been reported [2]. In those patients, the dysfunction was diagnosed an average of 7 months after the initiation of TDF therapy. All abnormalities normalized in all patients within an average of 5 weeks after drug discontinuation. Since in those patients, renal impairment was observed after 1–18 months of treatment, it was essential to analyse the long-term renal safety of TDF.

In this trial, TDF was not associated with nephrotoxicity and its renal safety profile was similar to that of d4T when either drug was administered in combination with 3TC and EFZ. As in the trial involving treatment-experienced patients (discussed above [2–4]), the patients in this trial had normal renal function at baseline.

Renal abnormalities are not uncommon in HIV-infected patients. They include renal insufficiency (6–10%), proteinuria [14,15] and electrolyte and acid–base disorders [16,17]. In a prospective study, 32% of 2057 HIV-positive women had proteinuria on initial evaluation [18]. Others have reported that hypophosphataemia is common in HIV patients (16.8%) [17,19]. Day and colleagues demonstrated that cumulative time on HAART and lopinavir/ritonavir but not TDF was strongly associated with hypophosphataemia—results which may have reflected treatment experience and the use of ‘salvage’ therapy [20]. Similarly, in our study, abnormalities were observed frequently in both the d4T and TDF arms (Tables 2 and 3). Proteinuria and haematuria were observed in 24 and 53%, respectively, of d4T-treated patients, and in a similar number of TDF-treated patients (Table 3). The incidence of hypophosphataemia was similar (7% over 3 years of therapy) in both TDF- and d4T-treated antiretroviral-naïve patients (Table 2). Those results indicate that renal abnormalities were not related to tenofovir treatment but to HIV disease. Interestingly, glycosuria was rare and of similar incidence in both groups of patients, thus suggesting that proximal tubulopathy is rare in HIV patients and that tenofovir in this study did not induce tubular damage.

Those data highlight that the use of a control group is necessary to distinguish between drug-related renal abnormalities and those which are due to HIV infection or co-morbid conditions.

Individual cases of proximal renal tubular dysfunction with or without renal failure have been reported. Most have occurred in patients with impaired renal function or those taking nephrotoxic agents [21]. In patients with pre-existing renal dysfunction (calculated creatinine clearances <50 ml/min), the dosing interval for TDF should be modified and the patients should be closely monitored [21].

Since TDF is transported efficiently by human organic anion transporter 1, and primarily eliminated by the kidneys, the co-administration of TDF with drugs that reduce renal function or compete for active tubular uptake or secretion, or both, may increase the serum concentration of TDF or increase the concentrations of other renally eliminated drugs.

In conclusion, from this 144-week, randomized, long-term, double-blind, placebo-controlled trial, we found no significant nephrotoxicity in treatment-naïve patients treated with TDF, and no differences in renal parameters between the TDF and d4T arms.

Conflict of interest statement. A.C. is an employee of Gilead Sciences and may hold stock or stock options.



   References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Tarantal AF, Marthas ML, Shaw JP, Cundy K, Bischofberger N. Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety and efficacy studies. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 323–333[Medline]
  2. Izzedine H, Isnard-Bagnis C, Hulot JS et al. Renal safety of tenofovir in HIV treatment experienced patients. AIDS 2004; 18: 1074–1076[CrossRef][ISI][Medline]
  3. Schooley RT, Ruane P, Myers RA et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002; 16: 1257–1263[CrossRef][ISI][Medline]
  4. Squires K, Pozniak AL, Pierone G Jr et al.; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 2003; 139: 313–320[Abstract/Free Full Text]
  5. Verhelst D, Monge M, Meynard JL et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002; 40: 1331–1333[CrossRef][ISI][Medline]
  6. Karras A, Lafaurie M, Furco A et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003; 36: 1070–1073[CrossRef][ISI][Medline]
  7. Reynes J, Peyriere H, Merle de Boever C, Le Moing V. Renal tubular injury and severe hypophosphatemia (Fanconi syndrome) associated with tenofovir therapy. 10th CROI, Boston, 2003 [abstract 717]
  8. Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D. Renal lesions in HIV-1-positive patient treated with tenofovir. AIDS 2003; 17: 935–937[CrossRef][ISI][Medline]
  9. Rollot F, Nazal EM, Chauvelot-Moachon L et al. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir–ritonavir–didanosine. Clin Infect Dis 2003; 37: 174–176[CrossRef]
  10. Lee JC, Marosok RD. Acute tubular necrosis in a patient receiving tenofovir. AIDS 2003; 17: 2543–2544[CrossRef][ISI][Medline]
  11. Coca S, Parazella Mark A. Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci 2002; 324: 342–344[CrossRef][ISI][Medline]
  12. Schaaf B, Aries SP, Kramme E, Steinhoff J, Dalhoff K. Acute renal failure associated with tenofovir treatment in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2003; 37: 41–43[CrossRef][ISI][Medline]
  13. Gallant JE, Staszewski S, Pozniak AL et al.; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. J Am Med Assoc 2004; 292: 191–201[Abstract/Free Full Text]
  14. Kimmel PL, Phillips TM, Ferreira-Centeno A, Farkas-Szallasi T, Abraham AA, Garrett CT. HIV-associated immune-mediated renal disease. Kidney Int 1993; 44: 1327–1340[ISI][Medline]
  15. Casanova S, Mazzucco G, Barbiano di Belgiojoso G et al. Pattern of glomerular involvement in human immunodeficiency virus-infected patients: an Italian study. Am J Kidney Dis 1995; 26: 446–453[ISI][Medline]
  16. Perazella MA, Brown E. Electrolyte and acid-base disorders associated with AIDS: an etiologic review. J Gen Intern Med 1994; 9: 232–236[ISI][Medline]
  17. Isnard-Bagnis C, Tezenas du Montcel S, Fonfrede M et al. Prevalence of electrolyte and acid–base disorders in HIV patients. J Am Soc Nephrol 2002; 13: 448A
  18. Szczech LA, Gange SJ, van der Horst C et al. Predictors of proteinuria and renal failure among women with HIV infection. Kidney Int 2002; 61: 195–202[CrossRef][ISI][Medline]
  19. Blick G, Greiger-R, Gordon T et al. Tenofovir may cause severe hypophosphatemia in HIV/AIDS patients with prior adefovir-induced renal tubular acidosis. Conference on Retroviruses and Opportunistic Infection, Boston, MA, 2003 [abstract 718]
  20. Day S, Leake Date H, Hankins M, Bannister A, Fisher M. Hypophosphataemia in patients taking Tenofovir. Brighton and Sussex University Hospitals. NHS Trust, Brighton, UK. 9th European AIDS Conference; 2003 October 25–29; Warsaw, Poland, Poster 9.7/4
  21. Viread EU. Summary of Product Characteristics. Gilead Sciences, Foster City, CA, 2004
Received for publication: 23. 6.04
Accepted in revised form: 13.10.04





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
20/4/743    most recent
gfh658v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (2)
Disclaimer
Request Permissions
Google Scholar
Articles by Izzedine, H.
PubMed
PubMed Citation
Articles by Izzedine, H.