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.
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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)