Tenofovir disoproxil fumarate (TDF) is currently among the most frequently prescribed antiretroviral agents in the United States and Europe. Prospective controlled clinical trials have not shown excess renal toxicity attributable to TDF [1,2]. Proximal renal tubular dysfunction (PRTD), usually associated with declining glomerular filtration rate (GFR), is a recognized and reversible complication of TDF treatment . The incidence of serious renal adverse events among more than 10 000 patients receiving TDF in the Viread Expanded Access Program was 1.5 per 1000 patient-years . Signs of PRTD may include hypokalemia, hypophosphatemia, proteinuria, normoglycemic glucosuria, renal tubular acidosis, and diabetes insipidus. Cirino and Kan  recently reported a case of TDF-associated hypokalemia and reviewed 39 others reported to the US Food and Drug Administration (FDA), including four deaths. The report did not provide sufficient detail to determine the spectrum of clinical manifestations attributable to hypokalemia, or whether hypokalemia was a cause of death. Therefore, we reviewed all cases of TDF-associated grade 3 (serum potassium 2.0–2.4 mmol/l) and grade 4 (serum potassium < 2.0 mmol/l) hypokalemia reported to Gilead Sciences Department of Safety and Public Health from clinical trials and from post-marketing pharmacovigilance spontaneous reports.
We identified 32 such reports from multinational sources between 2001 and 2006; 20 involved grade 3 and 12 grade 4 hypokalemia. One report did not include any evaluation for PRTD. Among the 31 evaluable cases, a diagnosis of Fanconi syndrome or other evidence of PRTD was present in 23 (74%). Of the remaining eight cases, six had other reasons for hypokalemia, such as diuretic or amphotericin use, vomiting, or diarrhea. One case presented with hyperkalemic acute renal failure and developed transient hypokalemia as renal function improved, and one case with unexplained hypokalemia resumed TDF without recurrence. Although many reports described symptoms such as weakness, fatigue and myalgia, only four cases reported medically significant complications of hypokalemia. Two (including case 1 in Cirino and Kan ) described profound muscle weakness manifesting as paralysis or inability to walk; these two cases and one additional case were also complicated by rhabdomyolysis. One case involved cardiac dysrhythmia (atrial tachycardia), which may have been caused by concurrent lung infection. All four cases improved with medical management and the discontinuation of TDF.
Six cases had a fatal outcome, including one reported by Cirino and Kan . Table 1 shows the cause of death and temporal relationship to hypokalemia and TDF use for these six cases and the three additional fatal cases associated with lesser grades of hypokalemia reported by Cirino and Kan . In no case did hypokalemia appear to contribute directly to death.
Cirino and Kan  noted among their cases a high prevalence of the concurrent use of ritonavir-boosted protease inhibitors, and stated that the concurrent use of ritonavir is a risk factor for TDF-associated nephrotoxicity. Whereas co-administration of lopinavir/ritonavir or atazanavir (with or without ritonavir) increases tenofovir exposure, no interaction with ritonavir alone has been demonstrated . Pharmacokinetic interaction studies performed with TDF and ritonavir co-administered with certain other HIV protease inhibitors have not demonstrated this interaction [7,8]. The statement that tenofovir secretion in the proximal renal tubule is mediated by multidrug resistance protein 2 is not supported by experimental evidence. Another renal transporter, multidrug resistance protein 4, is responsible for the efflux of tenofovir and this process is not inhibited by protease inhibitors [9,10]. It is unclear whether the association of ritonavir-boosted protease inhibitors with TDF-associated renal abnormalities is causal or if it is merely a marker of patients with more advanced HIV disease, who have a greater risk of many renal diseases associated with HIV [11,12] and an increased risk of toxicity from drugs that are renally eliminated. In an analysis of patients treated with TDF, lopinavir/ritonavir use was not associated with diminished GFR after controlling for other clinical variables .
These 32 reports of grade 3 or 4 hypokalemia occurred during more than 700 000 patient-years of TDF use. Although post-marketing surveillance underestimates the true incidence of adverse events, our review suggests that grade 3 or 4 hypokalemia during TDF use is rare. We also found that TDF-associated grade 3 or 4 hypokalemia usually occurs as a manifestation of PRTD, or is attributable to causes other than TDF. Therefore, hypokalemia and other manifestations of renal injury may be avoidable by adherence to published guidelines for TDF use [6,13].
The cases reported by Cirino and Kan  and many of those we reviewed contained insufficient detail to determine whether guidelines for the safe use of TDF were followed. Information about pre-existing renal disease, pretreatment or interval creatinine clearance, or TDF dosing were infrequently provided. In several of the cases we reviewed, however, the guidelines were not followed. Four (including two fatal cases) received concurrently the potent nephrotoxic agents amphotericin or cidofovir, which should be avoided with TDF [6,13], and another was a pediatric patient. TDF is not indicated for pediatric use . Three patients had pre-existing chronic kidney disease. To reduce the risk of TDF-associated renal injury, all HIV-infected patients should have GFR or creatinine clearance estimated at the initial medical evaluation and before the use of any medications that are renally eliminated, including TDF [6,13]. Periodic monitoring of renal function should be performed as part of routine care (e.g. every 3–6 months) and more often if renal function fluctuates [6,13,14]. TDF should be dose adjusted in the presence of stable chronic kidney disease (creatinine clearance < 50 ml/min)  to avoid the accumulation of drug that may increase the risk of toxicity. It should be discontinued if renal function is declining progressively and another cause of renal disease is not identified or signs of PRTD are present [6,13,14].
Potential conflicts of interest: The authors are employees of Gilead Sciences.
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