Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction.

Tenofovir was introduced as a second line drug for the treatment of human immunodeficiency virus (HIV) infection in India in December 2009. Although rare, renal toxicity is a recognized adverse drug reaction (ADR) of this drug, especially when administered with boosted lopinavir-ritonavir. In this case, an HIV positive patient receiving tenofovir based antiretroviral therapy (ART) for last 1 year developed albuminuria, glycosuria and hypophosphatemia. Renal function tests and random blood sugar were within normal limits. He was diagnosed as a case of tenofovir induced Fanconi syndrome. Tenofovir was discontinued and patient was prescribed an alternate regimen. Five months later clinical symptoms and renal functions returned to normal. A pharmacokinetic interaction between tenofovir and ritonavir may have resulted in the toxicity. A periodic monitoring of renal functions is desirable in patients on tenofovir based ART.

Introduction

Tenofovir, a nucleotide reverse transcriptase inhibitor is approved by US Food and Drug Administration for treatment of human immunodeficiency virus (HIV) infection in adults.[1] It is generally well tolerated (except for flatulence). However, rare episodes of acute renal failure and Fanconi syndrome have been reported.[23] Fanconi syndrome is a generalized defect in proximal renal tubule transport involving amino acids, glucose, phosphate, uric acid, potassium, bicarbonate and proteins. It can be due to outdated tetracycline, or drugs like gentamicin. cisplatin, valproic acid and tenofovir.[4] Here, we report a case of Fanconi syndrome probably induced by tenofovir.

Case Report

A 43-year old, HIV positive man was treated with stavudine, lamivudine and nevirapine as per National AIDS Control Organization (NACO) guidelines for 30 months. However, his CD4 count (56 cells/μL) and plasma viral load (1,27,734/mm of blood) failed to improve. Hence the patient was advised the second line antiretroviral therapy consisting of tenofovir 150 mg plus lamivudine 150 mg twice a day along with boosted lopinavir (LPV) 200 mg + 50 mg twice a day. He was also prescribed co-trimoxazole 960 mg once a day, along with multivitamins and folic acid. After a year on this therapy, patient complained of increased frequency of urination, ankle edema and knee pain. On investigations, serum creatinine and random blood sugar (RBS) were within the normal range. Urine examination showed albuminuria (1 g/L) and glycosuria (30 mmol/L) on two subsequent investigations on dates 28/09/2010, 27/10/2010. Serum phosphate was low (1.74, N: 2.7-4.5 mg/dL on 20/12/2010). His blood pressure was 118/78 mm of Hg, RBS was 132 mg/dL and radiological appearance of kidneys and urinary bladder was also normal. Considering the clinical presentation and time course of events the patient was diagnosed as a case of Fanconi syndrome.

Tenofovir was suspected to be the causal drug (Stopped on 5th January 2011) and patient was switched on alternative regimen consisting of abacavir 300 mg and lamivudine 150 mg, five tablets orally, twice a day, along with didanosine 400 mg at bed time on 5th January 2011. The boosted LPV was continued. After 5 months, increased urinary frequency, ankle edema and pain in knees were resolved and serum phosphate returned to normal level (2.8 mg/dL on 30/5/2011). Glycosuria become absent 1-month after the drug stopped, as investigations were done one dates 3/2/2011, 28/2/2011 and 27/6/2011. Albuminuria was absent when the patient was last followed up (27/6/2011). Causality assessment of the adverse drug event was carried out using WHO- Uppsala monitoring centre (UMC) criteria[5] and Naranjo's Scale.[6] Both the algorithms labeled tenofovir as “probable.” ADR was severe in nature as analysed on the Hartwig scale.[7] Further, the preventability assessment carried out using Modified Schumock and Thornton criteria[8] showed that the ADR was probably preventable.

Discussion

Tenofovir is the only nucleotide analogue approved for treatment of HIV infection. It is available as tenofovir disoproxil (prodrug) that has better oral bioavailability. In this case, the patient developed glycosuria, albuminuria and hypophosphatemia after receiving tenofovir based antiretroviral therapy for 1 year. The laboratory and routine clinical examination had ruled out the chronic kidney disease, diabetes and hypertension. A possibility of primary Fanconi syndrome was ruled out since the patient had no history suggestive of this condition during the past. The signs and symptoms appeared after 12 months of drug therapy. Tenofovir was discontinued and a regimen consisting of abacavir, lamivudine and didanosine along with lopinavir-ritonavir (LPV/r) combination was started. The patient recovered and renal functions returned to normal, hence, suggesting the possibility of tenofovir induced Fanconi syndrome.

Confirmed cases of Fanconi syndrome due to tenofovir have been reported worldwide.[239] In India also teneofovir associated renal dysfunction have been reported.[10] The mean duration of therapy with tenofovir before developing Fanconi syndrome is reported to be 11 months and it was discontinued in all these cases and subsequently renal function tests were normalized. An important observation made in all these patients was the concomitant treatment with boosted LPV. The risk of developing nephrotoxicty in patients prescribed tenofovir is nearly 4 times higher with boosted LPV than with nucleoside reverse transcriptase inhibitor (NRTI) based therapy.[11] Pharmacokinetic studies have shown that concomitant therapy with LPV/r increases the plasma concentration of tenofovir.[12] Tenofovir is predominantly secreted from the primary renal tubule via multidrug resistance (MDR-2) protein. This MDR-2 is located in the apical side of proximal renal cells. Ritonavir inhibits MDR-2 protein and leads to accumulation of tenofovir in primary renal tubules resulting in toxicity.[6] Proposed mechanism for this drug-induced proximal renal tubular toxicity include epithelial cell mitochondrial DNA depletion and/or direct tubular cytotoxicity.[11] Hence, it is hypothesized that drug interaction between tenofovir and LPV/r combination may be responsible for this adverse drug reaction (ADR). An effective management of this ADR is to stop tenofovir.

India has a large pool of HIV infected patients and NACO has recommended tenofovir as a second line antiretroviral drug. A substantial number of patients are prescribed this drug in combination with a protease inhibitor. It is therefore, recommended that patients receiving this combination should be screened for renal functions and electrolyte balance from the start of therapy and periodically during first year. This will ensure an early detection and management of the ADR.