Tenofovir (Viread) Associated with Mild Kidney Function Impairment, but not Clinically Relevant Renal Disease

By Liz Highleyman

The nucleotide reverse transcriptase inhibitor tenofovir (Viread, also in the Truvada and Atripla fixed-dose combination pills) is one of the most widely used HIV drugs, and is generally regarded as safe and effective. Yet there remains concern that the drug may cause kidney (renal) toxicity.

Tenofovir -- along with its relatives adefovir (Hepsera, used to treat hepatitis B) and cidofovir (Vistide, for CMV retinitis) -- is an acyclic nucleoside phosphonate that is excreted by the kidneys. Tenofovir can accumulate in, and potentially damage, the tiny renal tubules where blood is filtered and nutrients and water are reabsorbed back into the body. Symptoms of kidney injury can range from mildly elevated serum creatinine and low phosphate level to acute kidney failure.

Preclinical studies showed that high doses of tenofovir could cause kidney failure in animals, but the large randomized clinical trials that led to the drug's approval showed that kidney problems were rare; however, individuals with pre-existing kidney disease were excluded from those trials. Some subsequent case reports and cohort studies indicated that kidney toxicity does occur -- albeit uncommonly -- in people with pre-existing kidney impairment or other risk factors.

In the October 18, 2008 issue of AIDS, Joel Gallant and colleagues presented long-term follow-up data from 2 pivotal clinical trials, Gilead studies 903 and 934. In these studies, a total of 1111 treatment-naive participants were randomly assigned to receive tenofovir (n = 556) or a control thymidine analog NRTI (n = 555) -- either zidovudine (AZT; Retrovir) or stavudine (d4T; Zerit). Patients also took either lamivudine (3TC; Epivir) or emtricitabine (Emtriva) and efavirenz (Sustiva).

"Although it is reassuring that the overall risk for renal toxicity remains extremely low in published reports irrespective of study design, there are differences in renal outcomes when data from randomized controlled trials are compared with cohort studies," the authors wrote as background. "For this report, we specifically designed our analysis to improve the power and precision of assessing renal safety in 2 similarly designed randomized controlled trials that were originally powered and performed to test for efficacy."

Baseline characteristics were similar across treatment arms. Most participants were men, 21% were black (a group at higher risk for HIV-related kidney disease), and the median age was 36 years. At study screening, patients had serum creatinine less than 1.5 mg/dL, serum phosphorus level of at least 2.2 mg/dL, and an estimated glomerular filtration rate (GFR) by Cockcroft-Gault of at least 60 mL/min (in study 903) or at least 50 mL/min (in study 934).

Results

• Over 144 weeks of follow-up, patients taking tenofovir were significantly more likely to experience mild kidney impairment than those taking other control NRTIs.

• The proportion of patients who experienced confirmed abnormalities in serum creatinine (>1.5 mg/dL) or serum phosphorus (< 2.0 mg/dL) was less than 1% in both groups.

• Similar proportions in both groups experienced proteinuria (protein in the urine) of at least 100 mg/dL (tenofovir 5%; control NRTIs 6%).

• By the Cockcroft-Gault formula, the median change from baseline to week 144 in estimated GFR was -2 in the tenofovir group and +3 mL/min in the control NRTI group.

• By the modification of diet in renal disease (MDRD) formula, the corresponding changes were -2 and -1 mL/min per 1.73 m2, in the tenofovir and control groups, respectively.

• Decreases in GFR usually occurred during the first 96 weeks, and impairment did not progress over time.

• Among patients whose baseline GFR was in the lowest quartile of the population, renal function remained stable through 144 weeks in both groups.

• Among black patients, no significant difference in the change from baseline in estimated GFR was observed between treatment groups through 144 weeks.

• Among patients with mild renal impairment at baseline or taking medications for hypertension or diabetes, a statistically significant difference was seen in the changes in estimated GFR using the MDRD formula but not Cockcroft-Gault.

• Patients taking tenofovir were not more likely to experience serious or clinically relevant kidney problems.

• Overall, 28% of patients in the tenofovir group and 37% of patients in the control NRTI group discontinued the study regimen by week 144.

• No participants taking tenofovir discontinued therapy due to kidney problems, whereas 1 patient in the control NRTI group did so due to acute renal failure.

Based on these findings, the study authors concluded, "In two randomized, controlled trials, small differences in glomerular filtration rate over time were noted but no clinically relevant renal disease or adverse events were demonstrated in antiretroviral-naive patients treated with tenofovir through 144 weeks."

"Although this analysis clearly demonstrated the low incidence of clinically significant renal abnormalities through 3 years of antiretroviral therapy with a tenofovir-containing regimen, the findings presented here underscore the importance of evaluating renal function prior to and during antiretroviral therapy, particularly in high-risk populations, including elderly patients, patients with medical comorbidities, and patients taking multiple concomitant medications," they wrote in their discussion.

"Consideration of therapeutic alternatives or appropriate dosing interval adjustment is recommended for patients on tenofovir who develop impaired kidney function," they continued. "Moreover, as HIV-infected patients live longer, aging becomes an important risk factor for renal impairment. It is therefore important to encourage long-term prospective studies to evaluate kidney function in HIV-infected patients, including patients taking tenofovir, and to conduct research on more accurate measures of GFR in patients with normal kidney function."

Johns Hopkins University School of Medicine, Baltimore, MD; Mount Sinai School of Medicine, New York, NY; Orlando Immunology Center, Orlando, FL; Chelsea and Westminster Hospital, London, UK; Gilead Sciences, Foster City, CA.

10/14/08

Reference
JE Gallant, JA Winston, E DeJesus, and others. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS 22(16): 2155-2163. October 18, 2008.
(Abstract).