Tenofovir (TDF, Viread) has rapidly emerged as one of the most frequently used antiretroviral agents for the treatment of HIV infection. Much of the shift towards the use of tenofovir has occurred at the expense of stavudine (d4T, Zerit) and zidovudine (AZT, Retrovir) because of data demonstrating tenofovir's lower risk of mitochondrial toxicity compared to stavudine as well as better overall tolerability. However, nagging questions about the rate of tenofovir-related nephrotoxicity continue to trouble clinicians and have led to a number of investigations to address this issue.

The Recover study is a prospective, large, multi-center trial that involved an open-label switch from either stavudine or zidovudine to tenofovir in patients who were suffering from nucleoside-related toxicity. The data presented at this meeting was a substudy of the Recover study and it was performed in order to better gauge the risk of tenofovir-related nephrotoxicity in this large cohort of patients.

Recover Study

The Recover trial involved 1,350 patients who were switched to tenofovir from either stavudine or zidovudine because of nucleoside-related toxicity. Many of the patients on stavudine were switched in an attempt to improve lipids. This lipid switch data has been previously reported -- there was an average cholesterol reduction of 35 mg/dL in 70 patients switched to improve their cholesterol; the 94 patients who were switched because of hypertriglyceridemia had triglyceride levels reduced by 180 mg/dL.¹

This analysis examined the rate of kidney toxicity in patients following their switch to tenofovir. 1,193 patients were followed for a median of 36 weeks (12 to 48 weeks), which translated into 1,507 patient-years available for analysis.

Of these 1,193 patients on tenofovir, 5 developed acute renal failure. However, all of these patients had significant other risk factors for the development of kidney problems. Two of the 5 patients had baseline renal insufficiency with a creatinine clearance of less than 50 mL/min, but did not have their tenofovir dose reduced. Two patients had nephrolithiasis, one with obstructive uropathy that contributed to acute renal failure and the other with nephrocalcinosis from previous indinavir (IDV, Crixivan) treatment. The fifth patient had previous adefovir (Hepsera)-related renal toxicity.

The overall rate of discontinuation of tenofovir related to acute renal failure in this cohort was 0.4%, or 0.3 per hundred patient-years.

The outcome in most of these patients was favorable; 4 of 5 recovered after discontinuation of tenofovir. However, 1 patient with diabetes mellitus and baseline renal insufficiency had an acute myocardial infarction and died 2 days after the tenofovir was stopped.

Comment

This is one of the largest prospective studies of tenofovir and deserves attention. Although it was not primarily designed to assess renal toxicity, these data can help us better understand some of the risk factors and the rate of tenofovir-related renal dysfunction.

This study highlights the finding that in some cases of tenofovir-related renal toxicity, the dose of tenofovir is sometimes not appropriately reduced for patients who have baseline renal insufficiency. Patients with creatinine clearance under 50 mL/hour should have their tenofovir dose reduced to 300 mg three times per week. Since tenofovir is excreted by the kidneys, this excessive dosage may lead to higher tenofovir levels, and a subsequent downward spiral in renal function.

Footnote

1. Moreno S, Domingo P, Labarga P, et al. Dyslipidemia improvement in patients switching from d4T to tenofovir. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract H-855b.