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AIDS Patients on Tenofovir Must Be Monitored For Renal Failure Caused By Multiple Drug Interactions: Presented at ASN

By Maria Bishop

PHILADELPHIA, PA -- November 14, 2005 -- Tenofovir appears to be associated with multiple drug interactions that can lead to acute renal failure and chronic kidney disease that may not resolve upon withdrawal, researchers noted here at the 38^th Annual Meeting and Scientific Exposition of the American Society of Nephrologists (ASN).

In a presentation on November 10^th, Gregory L. Braden, MD, Chief, Renal Division, Baystate Medical Center, Springfield, Massachusetts, United States, and colleagues provided long-term follow-up (mean 14 months) data on five patients with tenofovir-associated acute renal failure (T-ARF),

Dr. Braden said multiple drug interactions with tenofovir are a serious threat to renal health, and frequent monitoring of renal function is warranted in any patient on tenofovir.

Tenofovir is a new nucleotide reverse transcriptase inhibitor used as rescue therapy for AIDS patients.

All of the five patients under this team's care developed advanced chronic kidney disease while on tenofovir. Three of these patients were taking at least two other drugs that interact with tenofovir (ritonavir, lopinavir, didanosine, atazanavir). In these three patients, the mean glomerular filtration rate (GFR) by creatinine clearance or Cockcroft-Gault before T-ARF was 81 mL/min (74-94 mL/min), but decreased to a mean of 13 mL/min (10-17 mL/min) with T-ARF. The GFR recovered only to a mean of 29 mL/min (19-37 mL/min) after discontinuation of tenofovir.

In the other two patients, the GFR decreased from 108 to 51 mL/min and 119 to 74 mL/minute, although it did return to baseline. Inadvertent rechallenge with tenofovir in one patient caused T-ARF to recur.

The five patients demonstrated classic acute tubular necrosis on urinary sediment or karyomegaly of proximal tubular nuclei on renal biopsy, Dr. Braden noted. This led the team to conclude that T-ARF manifests as acute tubular necrosis that may not resolve upon withdrawal of tenofovir.

Frequent monitoring of such patients should include checking renal function, blood urea nitrogen, serum creatinine, electrolytes, calcium, phosphorus and magnesium every two weeks for the first two months while on tenofovir with ritonavir, lopinavir/ritonavir, didanosine or atazanavir, noted Dr. Braden, and then monthly thereafter.

Dr. Braden and colleagues had previously analyzed their five patients along with 16 other T-ARF patients, concluding that T-ARF may be caused by a drug interaction of tenofovir with ritonavir or lopinavir/ritonavir.

In this more recent examination of T-ARF with additional drug interactions, the researchers added six newly reported cases for analysis to better characterize the condition, providing a total of 22 other patients for analysis since December 2002.

The team's analysis of these T-ARF patients revealed that mean serum creatinine increased from 0.9 to 3.9 mg/dL (P < .05) and decreased to 1.2 mg/dL in recovery (P < .05). Sixteen patients had Fanconis syndrome, which resolved in all patients. Recovery was associated with discontinuation of tenofovir in 22 patients.

Twenty-one patients were on ritonavir (alone or with lopinavir), 10 patients were on didanosine and five were on atazanavir.

The researchers also found that ritonavir increased tenofovir blood levels by 30%, by inhibiting renal tubular secretion of tenofovir via the multi-drug resistance associated protein-2 transporter.

In addition, the researchers reported that didanosine clearance is much greater than GFR, indicating renal tubular secretion. Tenofovir increases didanosine blood levels by 28%, possibly by competing with the human organic anion 1 transporter.

They also found that ritonavir increases the blood levels of atazanavir by 34%, and atazanavir increases the area under the curve of tenofovir by 24%, by unknown mechanisms.


[Presentation title: Tenofovir-Associated Acute Renal Failure & Chronic Kidney Disease: A Case for Multiple Drug Interactions. Abstract 896]

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