Antiretroviral Therapy

February 1, 2007

Tenofovir disoproxil fumarate is approved to treat HIV infection in combination with other antiretroviral agents. Although tenofovir is generally well tolerated, the potential for nephrotoxicity exists based on preclinical data, case reports, and observational studies.

Tenofovir disoproxil fumarate is approved to treat HIV infection in combination with other antiretroviral agents. Although tenofovir is generally well tolerated, the potential for nephrotoxicity exists based on preclinical data, case reports, and observational studies. Following its approval in the United States in October 2001, a series of case reports of tenofovir-related renal toxicity brought the issue to the attention of clinicians. While case reports raise the issue of nephrotoxicity, cohort studies and clinical trials have helped to clarify the overall safety profile of tenofovir. We present a review of the renal safety of tenofovir and provide a brief summary of the clinical implications of these data. [AIDS Reader. 2007;17:90-92, 99-104, C3]

Tenofovir disoproxil fumarate was approved in the United States in 2001, and later in the European Union and in 7 other countries, to treat HIV infection in combination with other antiretroviral agents. Tenofovir is a nucleotide analogue reverse transcriptase inhibitor structurally related to adefovir and cidofovir–2 drugs that have been associated with the development of clinically important renal dysfunction and hypophosphatemia.1,2

In preclinical studies of tenofovir, evidence of renal toxicity was noted in 4 animal species, with increases in serum creatinine and blood urea nitrogen levels; development of glycosuria, proteinuria, phosphaturia, and/or calciuria; and decreases in serum phosphate levels. These toxicities were noted at drug exposures–based on area under the time-concentration curve (AUC) data–that were 2 to 20 times higher than those observed in humans taking tenofovir at the standard dose.3

The role of multidrug resistance proteins (MRPs) has been central to the discussion of the potential nephrotoxicity of tenofovir. Tenofovir, cidofovir, and adefovir–all acyclic nucleoside phosphonates–are excreted by glomerular filtration and active tubular secretion. In the proximal tubule, cidofovir and adefovir interact with more than 1 renal transporter. These drugs enter renal cells on human renal organic anion transporter 1 (hOAT1) and exit on MRP2.

Until recently, it has been speculated that tenofovir-related nephrotoxicity is the result of MRP2 inhibition by protease inhibitors, especially ritonavir. However, recent studies have shown that MRP4, not MRP2, is the exit protein used by tenofovir.4

Commonly used drugs, including some NSAIDs (eg, indomethacin, indoprofen, ketoprofen) have been shown to inhibit MRP4.5 On the other hand, neither hOAT1 nor MRP4 are inhibited by pharmacologically relevant levels of protease inhibitors, including ritonavir (Figure). Because our understanding of the role of MRP4 is still evolving and there are no data to our knowledge on the concomitant use of NSAIDs in patients taking tenofovir, it would be prudent in future studies to assess the role of these agents in tenofovir's renal safety.

CLINICAL EXPERIENCE WITH TENOFOVIR
Information on the renal safety of tenofovir comes from case reports, cohort studies, and data from clinical trials. The definitions of renal toxicity vary depending on the study, with some using only serum creatinine (Cr) level to assess renal function, while others use glomerular filtration rate (GFR) estimated by the Cockcroft-Gault (CG) calculation of creatinine clearance (CLCr )6 or the Modification of Diet in Renal Disease (MDRD) Study Group equation.7 A summary of key outcomes from sources cited in this review, including methods used to measure renal function, is shown in Table 1.

Case Reports
A number of case reports have described proximal renal tubular dysfunction with8,9 and without10-12 Fanconi syndrome in patients taking tenofovir. Patients have presented with varying degrees of hypophosphatemia, normoglycemic glycosuria, proteinuria, increased Cr level, and decreased CLCrfrom 5 to 16 months after initiation of tenofovir. In 13 cases reported, 11 patients had either improvement or resolution of their renal events after discontinuation of the drug.8-12 Confounding variables in these case reports have included low body weight11 and extensive pretreatment with antiretroviral agents12 including adefovir.1 Others have implicated adefovir in proximal tubular dysfunction.1

In a retrospective review, Izzedine and colleagues13 described 19 cases of renal tubular dysfunction associated with the use of tenofovir before the recommendation that the dosing interval of tenofovir be adjusted based on estimated CLCr . Tubular dysfunction or renal failure (defined as more than a 25% rise in Cr level) occurred a mean of 6.9 months after starting tenofovir and normalized a mean of 4.7 weeks after stopping it. Four persons for whom CLCrhad been assessed before starting tenofovir were determined to have had preexisting renal insufficiency. The investigators concluded that renal dysfunction in treatment-experienced patients taking tenofovir appears to be a reversible event and is likely associated with preexisting renal insufficiency.

Clinical Trials

Manufacturer-Sponsored Randomized Trials The manufacturers of tenofovir have evaluated the renal safety of this agent in several controlled clinical trials.

Study 902.Study 902 examined the role of dose-related renal events with tenofovir in a population of treatment-experienced HIV-1–infected patients with suboptimal virologic suppression.14 This 48-week phase 2 study investigated the safety and efficacy of multiple doses of tenofovir (75, 150, and 300 mg once daily) versus placebo, in addition to the existing antiretroviral regimen. Participants had had substantial exposure to highly active antiretroviral therapy (mean, 55 months). There were no clinically significant renal abnormalities, and no patient discontinued the study treatment because of Cr elevations. The median Crvalues for the 4 groups remained constant at 0.9 mg/dL through 48 weeks of treatment, and no grade 2 or higher serum Cr elevations developed. No marked changes from baseline in median phosphorus levels occurred in any treatment group through week 24 or in the 3 tenofovir groups through week 48.

Study 907. Study 907 was a 48-week, phase 3, double-blind, placebo-controlled trial of tenofovir 300 mg daily added to a stable background antiretroviral regimen in 550 treatment-experienced HIV patients.15 Mean duration of antiretroviral therapy had been 5.5 and 5.3 years in the tenofovir and control groups, respectively. After 24 weeks, all patients received open-label tenofovir for the remainder of the study. The incidences of Cr elevations to more than 2.0 mg/dL and hypophosphatemia (serum phosphorus level less than 1.5 mg/dL) were similar in the tenofovir and placebo groups through 24 weeks and did not change through 48 weeks (0% and less than 1%, respectively). No patient withdrew from the study because of abnormalities in Cr level or serum phosphorus.

Study 903.Study 903 was a large, double-blind, active-controlled trial of tenofovir (n = 299) versus stavudine (n = 301)–both given with lamivudine and efavirenz–in treatment-naive patients.16 At baseline, all participants had Cr levels of less than 1.5 mg/dL, calculated CLCr equal to 60 mL/min, and serum phosphorus levels equal to 2.2 mg/ dL. Previous reports from this study showed no significant differences in changes in renal function from baseline between the groups through 144 weeks.16,17

Recently, a subanalysis of renal safety was performed using both the MDRD equation and the CG formula, which are better indicators of GFR than serum Cr level alone.18 There were no significant changes in GFR in the tenofovir group from baseline to week 144 by either method. There were no significant changes in GFR by either method in patients in either arm who were taking concomitant antihypertensive agents or diabetes medications.

No patient discontinued tenofovir as a result of a decrease in renal function, and no cases of Fanconi syndrome or proximal tubular dysfunction were identified through 144 weeks. Using the National Kidney Foundation criteria for staging chronic kidney disease,19 there were no significant differences between groups through 144 weeks. In a 48-week open-label extension of 171 patients rolled over to the tenofovir arm, GFR remained stable, with no GFR decrease greater than stage 2.

Study 934. Study 934 is an ongoing, randomized, open-label trial of tenofovir, emtricitabine, and efavirenz (n = 255) versus fixed-dose zidovudine/lamivudine plus efavirenz (n = 254) in antiretroviral-naive patients.20 At 96 weeks in the intent-to-treat analysis, there were no differences in graded serum Cr levels between the groups and no difference in median change in GFR from baseline. No patients in the tenofovir arm experienced 2 consecutive values of serum Cr level of greater than 1.5 mg/dL; 2 patients in the zidovudine arm experienced 2 consecutive values of serum Cr level of greater than 1.5 mg/dL. Participants in the zidovudine arm had significantly higher median GFR (MDRD equation) than those in the tenofovir arm (108 vs 100 mL/min/1.73m2, respectively; P = .006). GFR remained stable over 96 weeks in both arms, and there was no significant difference between the regimens in GFR as measured by the CG equation.

Other Randomized Trials
A prospective study conducted by Abbott Laboratories assessed the non–inferiority of once- (n = 115) versus twice-daily (n = 75) lopinavir/ritonavir plus tenofovir.21 After 96 weeks, 1 subject in each group demonstrated serum Cr levels greater than 3.0 mg/dL that returned to 1.7 mg/dL when study drugs were discontinued. Overall, for 98% of participants, the maximum Cr level was less than 1.5 mg/dL. None of the participants demonstrated new Cr elevations greater than 1.5 mg/dL after week 48.

The 96-week results of the BMS 045 trial shed some light on tenofovir renal safety in treatment-experienced patients.22 This trial compared atazanavir plus ritonavir or saquinavir with lopinavir/ritonavir–each with tenofovir and 1 other NRTI–in 358 treatment-experienced patients who had previously experienced virologic failure of at least 1 agent from each of the 3 major classes. The third arm of this trial (atazanavir plus saquinavir) was discontinued because of inferiority at week 24.

At 96 weeks, 67 patients remained in the atazanavir/ritonavir arm and 65 remained in the lopinavir/ritonavir arm; virologic responses remained comparable. Most patients who discontinued did so because of virologic failure: 33 and 24 in the atazanavir/ritonavir and lopinavir/ritonavir arms, respectively. Nine patients in the atazanavir/
ritonavir arm and 8 in the lopinavir/ ritonavir arm discontinued because of adverse events. Those patients who received atazanavir/ritonavir had significantly more jaundice and bilirubin elevations, while those who received lopinavir/ritonavir had more diarrhea. There was only a single grade 2 renal event (renal tubular acidosis), which occurred in the lopinavir/ritonavir arm.

Observational Cohorts and Other Comparative Studies
A large European cohort compared antiretroviral-naive patients with patients exposed to tenofovir- and non–tenofovir-containing regimens.23 Patients exposed to tenofovir had a lower probability of an elevated Cr level of greater than 1.4 mg/ dL (P < .001), and there was no significant difference between antiviral regimens after correcting for duration of exposure. A Cr level of greater than 1.4 mg/dL developed in 84 (8%) of the 1058 persons who were exposed to tenofovir, 75 of whom had other potential causes of renal impairment, including nephrotoxic drug exposure in 13 (15%), serious intercurrent illnesses in 21 (25%), and both in 10 (12%).

The 84 patients were then matched 1:1 with controls who were receiving tenofovir and who had a Cr level that remained in the normal range. There were no statistically significant differences in baseline Cror phosphate level measurements, nor were there differences in phosphate levels at the time of abnormal Cr levels. These data suggest that poorly controlled HIV has a detrimental effect on renal function.

The Johns Hopkins Clinical Cohort, a prospective observational cohort of HIV-positive patients who received antiretroviral therapy, assessed the effect of tenofovir (n = 344) versus other NRTIs (n = 314) on CLCr(CG equation).24 Patients were evenly distributed in both arms in terms of health status, median CD4 counts, and HIV RNA levels at study entry, although patients who received tenofovir had more antiretroviral experience and were less likely to be on an initial regimen. Median baseline Cr level was 0.8 mg/dL in each group, and CLCr was 117 and 118 mL/min in the tenofo-vir and other nucleoside groups, respectively.

After 1 year of follow-up, median estimated CLCr change was 213.3 mL/min in the tenofovir group and 27.5 mL/min in the NRTI group (P < .05). Patients in the tenofovir group had significantly greater decreases in the percentage of CLCr than did those in the NRTI group (210% vs 26%; P = .007). Multivariate analysis showed that tenofovir use and CD4+ cell count below 50/mL, but not diabetes, were significantly associated with CLCr decline (P = .006; P < .001; P < .06, respectively). There was no association with race, sex, HIV transmission factor, hypertension, or use of lopinavir/ritonavir or any other specific antiretroviral agent.

After 18 months of therapy, the median GFR change (MDRD equation) was 219 mL/min/1.73m2 in the tenofovir group and 211 mL/min/1.73m2 in the NRTI group.25,26 In a multivariate analysis, tenofovir use, duration of therapy, and lower CD4 count were associated with GFR decline (P < .05).24 There was no difference between groups at either time point in treatment discontinuations coincident with maximum decline in CLCr, suggesting that these changes were either not apparent to the clinicians or not considered to be clinically significant. The changes occurred in the normal range of GFR, however, and long-term follow-up will be necessary to determine whether they are clinically significant.

In retrospective cohort studies of tenofovir renal safety in 2 large HIV practices, mean baseline Cr level and calculated CLCr at the time tenofovir was initiated were 1.0 ± 0.2 mg/dL and 95 ± 29.0 mL/min, respectively.27 Of the 447 patients whose charts were reviewed, 434 (97%) had normal Cr levels at baseline. The mean Crand CLCr values were unchanged at 12 and 24 weeks. No grade 3 or 4 increases in Cr level were observed within 24 weeks of starting tenofovir. Grade 1 and grade 2 renal toxicities were noted in 6 patients (1.3%). Of the 6 cases of increased Cr level, 5 were attributed to other medical conditions, including concurrent use of nephrotoxic drugs in 4 patients and concurrent opportunistic infection in 2. Of the 13 patients (2.9%) with baseline Cr level greater than 1.5 mg/dL, Cr level decreased in 6 and remained stable in 5 while they were receiving tenofovir.

Mauss and colleagues28 performed a cross-sectional study that compared glomerular function in those who received and those who never received tenofovir-based regimens. GFR was estimated using serum cystatin C, an established GFR marker, and the MDRD formula. Patients who received tenofovir (n = 82) had a lower mean cystatin C clearance (86 ± 21 mL/min) than did patients never treated with tenofovir (n = 92) (97 ± 20 mL/min) (P < .01). A decreased cystatin C clearance (normal, greater than 80 mL/min) was observed in 28 patients (34%) who received tenofovir compared with 19 patients (21%) never treated with tenofovir (P = .06). Estimated CLCr (MDRD formula) did not detect this difference.

In addition, patients who received tenofovir had a higher mean protein content in urine (124 ± 110 mg/dL vs 94 ± 55 mg/dL; P < .05). In total, 30 patients (36%) who received tenofovir versus 15 control patients (16%) had a proteinuria greater than 130 mg/dL that was characterized by a tubular pattern with or without mild glomerular damage (P < .01). No patient had nephrotic or Fanconi-like syndrome. In a multivariate analysis, no association was found between renal function or proteinuria and the duration of antiretroviral therapy.

The authors concluded that tenofovir is associated with mild renal dysfunction when measured with sensitive methods such as cystatin C. In addition, proteinuria, mainly with a tubular pattern, was more frequently observed in patients treated with tenofovir. They suggested that this may render the kidney more vulnerable to concomitant treatment with nephrotoxic drugs, but long-term follow-up of this cohort will be required to determine the clinical significance.

Antoniou and colleagues29 conducted a retrospective cohort substudy of 172 patients enrolled in the tenofovir expanded access program (EAP). The participants received tenofovir for a median of 16 months (range, 3 to 25 months) with a minimum of 3 months of follow-up. During follow-up, grade 1 increases (greater than 0.5 mg/dL) in Cr level developed in 7 patients (4%) at a median of 334 days (range, 212 to 665 days) following initiation of tenofovir; no grade 2 or higher nephrotoxicity developed in any patient. Fifteen patients (8.7%) had an increase in Cr level of greater than 1.5 times the baseline value.

Although participants were treated with a variety of antiretroviral regimens, 114 (66.3%) were treated concurrently with lopinavir/ritonavir, which is known to raise tenofovir AUC by 32% in HIV-negative volunteers.30 By univariate analysis, neither duration of tenofovir treatment nor concurrent treatment with lopinavir/ritonavir was associated with a 1.5-fold increase in Cr level. Four patients (2.3%) dis-continued tenofovir because of increased Cr level and/or abnormal urinalysis results. The authors concluded that although slight increases in Cr level did occur after starting tenofovir, clinically significant nephrotoxicity was rare.

In a more detailed analysis, Nelson and coworkers31 reviewed the safety profiles of tenofovir in the manufacturer's global EAP before tenofovir was commercially available and from spontaneous safety reports submitted to the manufacturer through the first 4 years following commercial availability. A total of 10,343 patients were enrolled in the EAP from 12 countries, including the United States. Serum Crmeasurements were collected in more than 1600 patients in the EAP, and risk factors for development of graded Cr level abnormalities were determined using multivariate logistic regression models.

In the postmarketing safety database, adverse drug reactions, both serious and nonserious, received through spontaneous reporting up to April 30, 2005, were collected and analyzed. Reporting rates for individual serious adverse events (SAEs) were calculated. Based on estimates from sales data, 455,392 patient-years of exposure to tenofovir were documented.

The most common SAEs reported in the EAP were pneumonia (0.6%), renal events (0.5%), pancreatitis (0.5%), fever (0.4%), bacterial infection (0.3%), and lymphoma (0.3%). No individual SAE was reported in more than 1% of patients. Serious renal adverse events in the EAP and postmarketing data included renal failure (0.3% of patients; 0.50 cases/1000 patient-years, respectively), Fanconi/tubular disorder (0.05%; 0.43), and elevated Cr level (0.10%; 0.19). Risk factors for serious renal adverse events included concomitant nephrotoxic medications and low CD4+ cell count. Grade 3 or 4 elevations in Cr level were reported for 0.3% of 1699 patients in the EAP program. For postmarketing serious renal adverse events with Crdata, the median maximum serum Cr level was 2.3 mg/dL and median time to resolution to grade 2 or less was 29 days. Mitochondrial toxicity, neuropathy, and bone fractures were reported infrequently in the EAP (less than 0.1%) and postmarketing databases.

A study by Winston and coworkers32 included all patients who received combination antiretroviral therapy at a hospital-based practice in Australia. Of the 948 participants, 290 were receiving tenofovir-containing regimens, 618 were on other regimens, and 40 had received tenofovir in the past. A review of the time-weighted change in Cr level, CLCr (CG equation), and anion gap indicated that there was no significant difference in the serum Cr level between groups; however, there was a small decline in CLCr (25.6 mL/min; P = .010) and an increase in anion gap (0.53; P < .001) in the tenofovir-treated patients. Only 2 patients discontinued therapy because of tenofovir-related renal insufficiency.

By multivariate analysis, independent predictors of a decline in renal function were use of tenofovir and a lower baseline CLCr . The results of this study are similar to those of Gallant and colleagues24-26 and show a small decline in GFR associated with tenofovir use, but with GFR remaining well within the normal range.

Finally, Padilla and colleagues33 cite their "real-world" experience with tenofovir renal safety in a retrospective case-control study of 122 consecutive tenofovir-naive patients treated with tenofovir-containing regimens, and 194 patients who received antiretroviral therapy with other drugs. During a 12-month period, grade 1 or higher serum Cr elevations developed in 5 patients (4.1%) in the tenofovir group and in 1 (0.5%) in the control group (P = .018). Only 2 patients (1.6%) discontinued tenofovir as a result of serum Cr level elevations. In 4 of the 5 patients in whom Cr elevations developed, tenofovir was combined with lopinavir/ritonavir.

CLINICAL IMPLICATIONS AND RECOMMENDATIONSScreening and Initial Evaluation
Recently published guidelines from the HIV Medicine Association of the Infectious Diseases Society of America recommend that at the time of HIV diagnosis, all patients should be assessed for kidney disease.34 This includes a screening urinalysis for proteinuria (urine dipstick) and an estimate of GFR using either the CG or MDRD method.34,35 Renal function should also be assessed before beginning therapy with any antiretroviral agent and should be repeated periodically while the patient is receiving therapy.34

If there is no evidence of proteinuria at initial evaluation, patients at high risk for the development of proteinuric renal disease (eg, African Americans; those with CD4+ cell counts of less than 200/µL or HIV RNA levels greater than 4000 copies/mL; or those with diabetes mellitus, hypertension, or hepatitis C virus coinfection) should be screened annually. Patients with proteinuria greater than 1+ by dipstick or reduced renal function (GFR, less than 60 mL/min/1.73 m2) should be evaluated further with renal ultrasonography and protein/creatinine ratio determination and referral to a nephrologist should be considered.34

Patient Management
Tenofovir is excreted by the kidneys through a combination of glomerular filtration and active renal tubular secretion. Coadministration of tenofovir with drugs that are eliminated by tubular secretion may increase serum concentrations of either tenofovir or the coadministered drug because of competition for this elimination pathway. Ideally, tenofovir should be avoided with the current or recent use of a nephrotoxic agent3 or agents eliminated by active tubular secretion (eg, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir). Patients receiving tenofovir who have a GFR of less than 90 mL/min/1.73m2; who are receiving agents eliminated by tubular secretion; or who have comorbid conditions (eg, diabetes, hypertension) should have renal function monitored (CG or MDRD method), urinalysis for protein and glucose, and serum phosphorus determinations twice yearly as a minimum, according to Gupta and colleagues.34

An additional subgroup of patients taking tenofovir with atazanavir or lopinavir/ritonavir should be monitored closely for tenofovir-associated adverse events.3 This recommendation is based on pharmacokinetic studies showing that tenofovir exposure is increased by 32% when it is coadministered with lopinavir/ritonavir with no change in lopinavir or ritonavir levels30 and that coadministration of atazanavir results in comparably increased exposure to tenofovir and decreased exposure to atazanavir.36 Coadministration of tenofovir with either cidofovir or adefovir is not recommended. While Gupta and colleagues34 recommend twice-yearly screening as a minimum, providers should consider assessing these parameters at every routine visit, usually 3 or 4 times a year.

Antiretroviral Therapy and Dosage Adjustments
In chronic kidney disease, dosage adjustments of tenofovir should be made using CLCr determinations according to recommendations in the product labeling (Table 2). Because studies of medication dosing in renal failure have traditionally used the CG equation, it is appropriate to use this method when making dosage adjustments.35

Although infrequent, when acute or progressive renal failure occurs in patients receiving tenofovir, the drug should be discontinued and another agent substituted. Antiretroviral agents should not be withheld from patients because of the severity of their renal disease.34 The patient's renal function should continue to be monitored. In general, nephropathy associated with tenofovir is reversible once the drug is discontinued. Since acute renal function changes in HIV disease can be multifactorial, other causes of renal dysfunction should be considered and comorbidities such as blood pressure should be controlled.34

SUMMARY
Cohort studies and clinical trials have helped to put case reports of renal dysfunction with tenofovir use into context. Clinical trial data show that in patients who have normal baseline renal function, the incidence of clinically significant tenofovir-related renal dysfunction is extremely low. While cohort studies suggest that tenofovir may be associated with a small decline in renal function when it is estimated by calculated CLCr , these studies also demonstrate that in clinical settings outside clinical trials, renal function generally remains within the normal range and that discontinuations as a result of renal toxicity are uncommon. Accurate patient assessment and follow-up can help distinguish between renal events related to therapy and those related to HIV disease and other factors. In addition, validated methods of estimating renal function, such as CG and MDRD, are available and should be used to assess patients before and during antiretroviral therapy.

Dr Sax has been a consultant for Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Vertex; has received grant/research support from Bristol-Myers Squibb, Merck, and Pfizer; and has received honoraria from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Merck, and Vertex. Dr Gallant has been a consultant for Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Vertex, Tibotec, and Monogram Biosciences; has received grant or research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Pharmaceuticals, and Tibotec; and has received honoraria from Abbott Laboratories, Gilead Sciences, and Monogram Biosciences. Dr Klotman has been a consultant for Gilead Sciences.

In exception to the Journal's editorial policy, the manufacturer of tenofovir disoproxil fumarate, Gilead Sciences, provided assistance in the preparation of this manuscript.

References:

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