aDepartments of Nephrology, France
bVirology Laboratory, France
cInfectious Diseases, Pitie-Salpetriere Hospital, France
dDepartment of Pharmacology, Bichat Claude Bernard Hospital, France
eDepartment of Hepatology, Pitie-Salpetriere Hospital, Paris, France.
Received 4 July, 2009
Revised 14 July, 2009
Accepted 27 July, 2009
Correspondence to Dr Hassane Izzedine, Department of Nephrology, La Pitié-Salpêtrière Hospital, 47-80 Boulevard de l'Hôpital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France. E-mail: email@example.com
Tenofovir disoproxil fumarate (TDF) is the first nucleotide reverse transcriptase inhibitor used in the management of HIV, hepatitis B and HIV/hepatitis B coinfected individuals, particularly when resistance to other agents exists. Fanconi syndrome has been infrequently observed in TDF-treated patients. We hypothesized that probenecid may protect against recurrence of nephrotoxicity in these patients.
Three white male, HIV/hepatitis B virus (HBV) coinfected patients with a past history of nephrotoxicity related to TDF, who failed previous treatment of chronic hepatitis B, were re-treated with TDF (300 mg daily) in combination with probenecid (500 mg daily) after giving written informed consent. TDF plasma concentration (normal value 22–66 ng/ml) was measured using a validated HPLC assay with fluorimetric detection . HBV serological markers were determined using Architect Abbott's tests (Abbott, Les Ulis, France). Plasma HBV DNA was measured by real time PCR using HBV COBAS AmpliPrep - COBAS TaqMan (Roche, Meylan, France) as previously described . Biological tests including full blood count, renal function (serum creatinine, creatinine clearance by Cockcoft and Gault formula, a modification of diet in renal disease formula, and urinary creatinine clearance estimation urine to plasma ratio of creatinine), proximal tubular function surrogates [serum electrolytes measurement: sodium (Na), potassium (K), urea, creatinine, bicarbonate, phosphorus and uric acid as well as urinary measurement of pH, Na, K, glucose level, proteinuria and aminoaciduria] were realized before starting TDF. Table 1 summarizes the evolution of these parameters.
These tests alongside with monitoring of plasma TDF were repeated weekly during the first month and then every 2 weeks for the following month and monthly thereafter.
For patient one, initial introduction of TDF resulted in a significant drop in the HIV and HBV viral loads within 4–6 months, respectively. However, 20 months later, he presented generalized Fanconi syndrome. All anomalies normalized within 4 weeks of TDF discontinuation. HBV-DNA level increased rapidly to their initial level 1 month later. Decompensated lamivudine resistant HBV-related cirrhosis was diagnosed and TDF/probenecid combination started. From baseline to week 24, HBV viral load decreased by 1.5 log and 2.4 log from baseline to months 6 and 22, respectively. Plasma HIV-1 RNA levels remained below the limit of detection and the CD4 cell count increased by 50% compared with baseline. No stigmata of Fanconi syndrome were found and no TDF dosage adjustment was performed during the follow up. In October 2008, the patient underwent a liver transplant with a HBV viral load of 1.5 log. TDF/probenecid were stopped. Three months after liver transplantation, the patient was clinically well with perfect virological control and without renal anomalies.
Patient two had developed Fanconi syndrome and acute tubular necrosis (serum creatinine, 1.36 mg/dl), 1 month after TDF initial use. Despite undetectable HIV and HBV viral loads, TDF was withdrawn and replaced by adefovir and lamivudine and entecavir since a lamivudine-resistant YIDD mutant strain of HBV was detected. All abnormalities except renal function normalized within 4 weeks after TDF discontinuation. Although HIV infection remained controlled, the patient developed HBV-related cirrhosis. TDF/probenecid combination was restarted. HBV viral load showed a drastic 4.1 log decrease (66%), whereas HIV-1 RNA remained undetectable. The CD4 cell count stabilized. Neither acute kidney injury nor proximal tubular dysfunction reoccurred during the 24-month follow-up, despite comparatively higher TDF serum levels (90–250 ng/ml).
Past history of patient three was remarkable for early Fanconi syndrome and acute kidney injury (serum creatinine, 3.46 mg/dl) under TDF, which disappeared 1 month after it was stopped. HBV viral load, well controlled under TDF containing regimen, consequently increased.
A trial of reuse was made. Twelve days later, Fanconi syndrome and acute renal failure reoccurred. TDF plasma level was in normal range, 40 ng/ml.
TDF was then replaced by the association lamivudine/entecavir/adefovir without HBV control, thus leading to liver cirrhosis. A TDF/probenecid combination was introduced. From baseline to month 3, HBV viral load showed a drastic 2.9 log decrease. TDF plasma levels were in the toxic range (209 ng/ml) and TDF dose reduced to 300 mg thrice a week according to recommendations with creatinine clearance. Probenecid was maintained at one tablet per day. This patient who previously experienced an early recurrence of proximal tubulopathy after TDF re-introduction had no renal abnormalities during an 18-fold longer duration under a TDF/probenecid combination. Moreover, a progressive decrease in HBV viral load (−2.8 log during 13 months) was noted.
Overall, during the follow up of these patients, we did not observe the emergence of a particular mutation that could potentially be selected by TDF treatment.
TDF is uptaken into proximal tubular cells via the basolateral organic anion transporter (OAT) and is extruded by the apical multidrug resistance protein. TDF nephrotoxicity may be caused either by an excessive cell uptake or a disturbed extrusion outside the proximal tubular cells. TDF, cidofovir and adefovir are all substrates of human-OAT 1 (hOAT1) . Oral probenecid, a typical inhibitor of hOAT1, protects against nephrotoxicity and decreases renal clearance in monkeys that are receiving chronic intravenous cidofovir treatment  and likewise could limit the TDF renal toxicity.
TDF/probenecid combination seems to avoid TDF nephrotoxicity in susceptible patients.
1. Cundy KC, Sueoka C, Lynch GR, Griffin L, Lee WA, Shaw JP. Pharmacokinetics and bioavailability of the antihuman immunodeficiency virus nucleotide analog 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs. Antimicrob Agents Chemother 1998; 42:687–690.
2. Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001; 358:718–723.
3. Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K. Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res 2007; 24:811–815.
4. Lacy SA, Hitchcock MJ, Lee WA, Tellier P, Cundy KC. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 1998; 44:97–106.
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