Changes in Renal Function Associated with Tenofovir Disoproxil Fumarate Treatment, Compared with Nucleoside Reverse-Transcriptase Inhibitor Treatment

Clinical Infectious Diseases, Apr 2005

In our large observational cohort, use of tenofovir disoproxil fumarate (n = 344) was associated with a greater decline in renal function than was use of alternative nucleoside analogues (n = 314). Other associations included a lower CD4 cell count, decreased renal function at baseline, and diabetes. The declines were modest and did not lead to greater rates of discontinuation of therapy.

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Changes in Renal Function Associated with Tenofovir Disoproxil Fumarate Treatment, Compared with Nucleoside Reverse-Transcriptase Inhibitor Treatment

CID Changes in Renal Function Associated with Tenofovir Disoproxil Fumarate Treatment, Compared with Nucleoside Reverse-Transcriptase Inhibitor Treatment Joel E. Gallant 0 Michelle A. Parish 0 Jeanne C. Keruly 0 Richard D. Moore 0 0 The Johns Hopkins University School of Medicine , Baltimore, Maryland , USA In our large observational cohort, use of tenofovir disoproxil fumarate (n p 344) was associated with a greater decline in renal function than was use of alternative nucleoside analogues (n p 314). Other associations included a lower CD4 cell count, decreased renal function at baseline, and diabetes. The declines were modest and did not lead to greater rates of discontinuation of therapy. - Tenofovir disoproxil fumarate (TDF) is the first nucleoside reverse-transcriptase inhibitor (NRTI) approved by the US Food and Drug Administration for the treatment of HIV disease. It is renally excreted via a combination of glomerular filtration and active tubular secretion. Adefovir dipivoxil, a related NRTI, caused proximal renal tubular dysfunction at a dosage of 60– 120 mg/day, which is required to inhibit HIV replication [ 1 ]. However, in clinical trials, TDF has demonstrated an excellent renal safety profile. In the Gilead Sciences 903 trial, in which 299 treatment-naive patients received TDF in combination with lamivudine and efavirenz, there were no instances of renal failure or grade 3/4 elevations in the serum creatinine level through 144 weeks, and there were no significant differences in renal function, compared with that of patients taking stavudine [ 2, 3 ]. Nevertheless, renal impairment, including but not limited to proximal renal tubular dysfunction, has been reported to be associated with TDF use [ 4–11 ]. The majority of cases of renal impairment have occurred in patients with underlying systemic between the mean value at baseline with the mean value at each time interval for the 2 groups. Results. A total of 344 patients received TDF, and 314 patients received an alternative NRTI. The characteristics of the sample are shown in table 1. There were no substantive differences between the groups, except for the expected greater use of alternative NRTIs in the NRTI group, the greater use of lopinavir-ritonavir in the TDF group, and the greater use of efavirenz among patients receiving NRTIs. It is now recommended that the dosing interval of TDF be modified for patients with a CLCr of !50 mL/min [ 14, 15 ]. Only 2 patients, who had a serum creatinine level of 12.0 mg/dL at baseline, received !300 mg of TDF per day. Table 2 shows serum creatinine levels and CLCr at baseline and changes in serum creatinine levels and CLCr over the period of treatment. The TDF group had significantly greater increases in serum creatinine levels and decreases in absolute and percentage CLCr, compared with the NRTI group. There was no difference in the rate of discontinuation of treatment coincident with maximum decline in CLCr: only 19 (5.5%) of TDF-treated patients and 21 (6.7%) of NRTI-treated patients discontinued therapy at the time of maximum decline in renal function. Figure 1 shows the change in CLCr from the start of treatment through day 365 of therapy (in 90-day increments). It can be seen that the change in CLCr was apparent after 90 days of therapy and persisted for the entire year. In addition, regarding the comparison of TDF use with use of other NRTIs, diabetes was associated with a 13% change in CLCr (vs. a change of 8% in patients without diabetes [P ! .04]); a baseline CD4 cell count of !50 cells/mm3 was associated with a change of 14% (vs. a change of 8% for patients with a baseline count of 150 cells/mm3 [P ! .01]); a baseline HIV-1 RNA load of 120,000 copies/mL was associated with a change of 15% (vs. a change of 8% for patients with a baseline load of 120,000 copies/mL [P ! .02]); and receipt of initial HAART was associated with a change of 11% (vs. a change of 8% for patients who received HAART subsequently [P ! .03]). Hypertension status, age, sex, ethnicity, the presence of concomitant hepatitis C or B, use of lopinavir/ritonavir, or use of any other specific protease inhibitor or NRTI were not associated with the percent change in CLCr (P 1 .05). Adjusting for these variables in a multivariate analysis, only TDF use (P p .006) and a CD4 cell count of !50 cells/mm3 (P ! .001) were associated with CLCr decline. A baseline CLCr value of !50 mL/min and diabetes were less strongly associated (P p .10). Because the dosage of TDF was only adjusted for poorer renal function (defined as a CLCr of !50 mL/min) in 2 patients, the multivariate analysis was repeated for those patients with a baseline CLCr of 150 mL/min. The results were similar; TDF use (P p .004), a low CD4 cell count (P ! .001), and diabetes (P p .06) were associated with CLCr decline. In both analyses, hypertension status, use of lopinavir-ritonavir or other antiretroviral agents, HIV-1 RNA load, previous use of adefovir d (...truncated)


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Gallant, Joel E., Parish, Michelle A., Keruly, Jeanne C., Moore, Richard D.. Changes in Renal Function Associated with Tenofovir Disoproxil Fumarate Treatment, Compared with Nucleoside Reverse-Transcriptase Inhibitor Treatment, Clinical Infectious Diseases, 2005, pp. 1194-1198, Volume 40, Issue 8, DOI: 10.1086/428840