In October 2001, tenofovir disproxil fumarate (TDF) was approved by the United States Federal Drug Administration as the first nucleotide analogue reverse transcriptase inhibitor to be used in the treatment of HIV infection . Clinical trials in which TDF use was evaluated in humans showed the drug to be well tolerated, effective against partly nucleoside analogue reverse transcriptase (NRTI)-resistant HIV strains, exerting antiviral activity against hepatitis B virus and causing less mitochondrial and metabolic toxicity than other NRTI.
These characteristics led to the relatively widespread use of TDF soon after it became available. However, another characteristic of TDF led clinicians and researchers to monitor and evaluate kidney function in TDF recipients. TDF is structurally related to cidofovir and adefovir, two compounds that have been associated with renal toxicity caused by the tubular accumulation of toxic metabolites.
In the literature, multiple case reports and small case series have linked the use of TDF with the onset of acute renal failure . However, in the past 2 years observational and cross-sectional studies evaluating the renal function of patients on treatment with TDF were published. Jones et al.  evaluated the renal function of 1058 HIV-seropositive patients treated with TDF from the Chelsea and Westminster cohort: 84 (8%) had a serum creatinine level above 120 μmol/l, and alternative etiology for renal function abnormality was found in 90% of these individuals. In a double-blind, randomized active-controlled trial, Izzeddine et al.  found no differences in serum creatinine values between stavudine and TDF recipients at 144 weeks post-enrollment. In an observational trial, Gallant et al.  found that a year after patients were started on a TDF-containing regimen, they had a 10% decline in their creatinine clearance compared with a 6% decline in creatinine clearance observed in patients started on other NRTI-containing regimens (P = 0.007). Obviously, the differences in methodology of the above-mentioned trials can partly explain the differences in the findings.
We attempted to evaluate the effect of the use of TDF on the renal function of HIV patients at Thomas Street Health Center in Houston, Texas. The center is a multidisciplinary, outpatient clinic that provides medical care to HIV-seropositive, mostly indigent, individuals in the Harris County area. TDF became available in our clinic in 2001, and became the most frequently prescribed antiretroviral in our patient population in 2004.
The study is a retrospective, cross-sectional analysis of serum creatinine changes of patients who were on a TDF-containing HAART regimen between January 2003 and December 2004. During the study period we identified all patients who received TDF from our pharmacy and who met the following criteria: (1) a serum creatinine value was available at 0–90 days before the initiation of TDF (baseline value); and (2) a serum creatinine value was available 24 months after the initiation of therapy or upon discontinuation. We calculated the frequency of patients who had the following increases in serum creatinine over their baseline value: grade 1, 0–25.0%; grade 2, 25.1–50.0%; grade 3, 50.1–75.0%; grade 4, 75.1–100%; grade 5, greater than 100% increase in serum creatinine.
We reviewed the medical records of any patient who had discontinued TDF during the study period or had a doubling in serum creatinine (grade 5). Medical records were reviewed to collect data on co-morbid conditions and concomitant nephrotoxic drugs.
A total of 594 patients were on TDF as part of their treatment regimen in January 2003. Fifty-eight patients did not have a baseline serum creatinine value and 30 patients did not have a serum creatinine value at follow-up. During these 2 years of follow-up, 18 patients discontinued TDF-based therapy less than 24 months after the initiation of therapy. The reasons for the discontinuation were: loss to follow-up (15 patients); rise in serum creatinine (two patients); and no reason specified in the medical records (one patient).
Of the evaluable 488 patients, there were 263 patients (53.8%) who either had a decline or no change in serum creatinine. The change in serum creatinine over 24 months was grade 1 in 163 patients (33.4%), grade 2 in 43 patients (8.8%), grade 3 in 11 patients (2.2%), grade 4 in four patients (0.8%), and grade 5 in five patients (1.0%).
We reviewed the medical records of patients with grade 5 renal toxicity for the presence of co-morbid conditions that may predispose to renal insufficiency. Of the five patients with grade 5 renal toxicity, two patients had a diagnosis of diabetes mellitus and hypertension, one patient had a diagnosis of hypertension, and two patients had no co-morbid conditions.
The cutoff for an abnormal serum creatinine value at our laboratory is 1.3. A total of 27 patients were started on TDF with an abnormal baseline serum creatinine value. Of these patients, 15 (55.5%) had no change or a decline in serum creatinine, whereas six (22.2%), three (11.1%), two (7.4%) and one (3.7%) patients had grade 1, 2, 4, and 5 changes in serum creatinine, respectively, 24 months after the initiation of TDF-based therapy. Patients with abnormal creatinine levels at baseline were not more likely to develop renal toxicity of any grade (P = 0.8). However, among patients who developed toxicity, those who had abnormal levels at baseline had higher grade toxicities (P = 0.02) when toxicity was analysed as a continuous variable via logistic regression.
We analysed the serum creatinine changes in 488 patients on TDF-based antiretroviral treatment over a 24-month period. We found that significant renal toxicity (doubling of serum creatinine) occurred in 1.0% of the general clinic population and in 3.7% of the patients who had abnormal serum creatinine values at baseline. Of the patients who had grade 5 renal toxicity, 60% had co-morbid conditions that predisposed them to renal insufficiency.
The above data could be an overestimate of renal toxicity because many HIV patients gain weight after successful virological suppression. Therefore, increases in serum creatinine could merely signify an increase in lean body weight, and changes in creatinine clearance are a better estimate of renal toxicity in this population.
Whereas the long-term use of TDF-based therapy was found to be generally safe in our population, the fact that among patients who developed toxicity, those who had baseline abnormal serum creatinine levels tended to develop higher grade toxicity warrants the continuous monitoring of renal function in this patient subpopulation.
The authors would like to thank the Harris County Hospital District, Office of Research.
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