December 16, 2005
Treatment with antiretroviral agents is often fraught with a host of adverse effects. An emerging topic of great concern within the field of anti-HIV treatment relates to the fact that certain nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), particularly tenofovir (TDF, Viread), might be associated with nephrotoxicity that impairs kidney function and ultimately leads to kidney failure.
To evaluate whether an association exists between tenofovir treatment and nephrotoxicity, the current study, led by Joel Gallant, M.D., M.P.H., assessed the glomerular filtration rate (GFR) of patients participating in the Gilead 903 study. Patients were randomized to receive either tenofovir + lamivudine (3TC, Epivir) + efavirenz (EFV, Sustiva, Stocrin) or stavudine (d4T, Zerit) + lamivudine + efavirenz over the course of three years.
The GFR is an indicator that is calculated using the patient's age, weight, gender, body size and serum creatinine level, and can be used to monitor the renal function of patients. The investigators of this study, who also played a lead role in the Gilead 903 study, calculated the GFR using two classical estimation methods: the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations.
Prior results from the Gilead 903 study demonstrated that both treatment arms conferred impressive anti-HIV activity following the completion of 144 weeks of therapy; however, less overall toxicity was associated with the tenofovir-containing arm as opposed to the stavudine-containing arm.
Further analysis of Gilead 903 participants in the current study revealed that patients receiving either tenofovir or stavudine possessed similar renal profiles at baseline and throughout the three years of treatment.
No patients in either treatment arm developed Fanconi syndrome or proximal renal tubular dysfunction throughout 144 weeks of observation, and no individual had to discontinue therapy due to tenofovir-related renal abnormalities during this time.
Moreover, no differences were reported between the two arms for several measurements assessing abnormal kidney function, including serum creatinine, serum phosphorus, urine protein and urine glucose. Perhaps most importantly, the incidence of stage 1-5 kidney disease (as per the National Kidney Foundation [NKF] classifications) was virtually identical between the two treatment arms when the GFR was calculated using the MDRD equation (P = .553).
NKF Chronic Kidney Disease Stages 1 to 5 Through Week 144
Maximum Confirmed Stage|
Through Week 144
|TDF + 3TC + EFV|
(n = 293)a
|d4T + 3TC + EFV|
(n = 294)a
|Stage 1 (GFR > 90 mL/min)||69%||71%|
|Stage 2 (GFR 60-89 mL/min)||30%||27%|
|Stage 3 (GFR 30-59 mL/min)||1%||1%|
|Stage 4 (GFR 15-29 mL/min)||0%||< 1%|
|Stage 5 (GFR < 15 mL/min)||0%||0%|
|a. Number of patients with at least 2 post-baseline measurements|
Use of either the MDRD or CG equation to assess the GFR yielded similar results.
The results of the Gilead 903 study conclusively demonstrate that the incidence of chronic kidney disease at various stages of severity was similar with both tenofovir and stavudine treatment during 144 weeks of observation.
The current findings are significant in that they establish that tenofovir is safe in regard to kidney function and highlight the overall low incidence of nephrotoxicity in both study arms. Although stavudine did not cause nephrotoxicity to any appreciable extent, it should be remembered that this compound has been more closely associated with increased levels of mitochondrial toxicity and lipoatrophy than virtually all other members of the NRTI family of drugs.
This very well controlled clinical study should allay any worry regarding tenofovir-related nephrotoxicity while emphasizing that such clinical concerns have probably been exaggerated.
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