In the April 15 edition of Clinical Infectious Diseases doctors from Portland, Oregon, report the death of a man taking a HAART regimen containing tenofovir and ddI from kidney failure and lactic acidosis. Although the man had pre-existing impaired kidney function, this case adds to the growing body of evidence that tenofovir can be toxic to the kidneys and adds to cautions about the use of tenofovir and ddI together in people with impaired renal function.
Clinical trials, which led to the licensing of tenofovir, found no evidence of kidney toxicity. However, early trials of the drug on animals suggested that large doses could cause kidney failure, and patients with impaired kidney function were excluded from the drug’s human trials.
Tenofovir is cleared from the body by the kidneys and Gilead, manufacturer of the drug, recommend that the drug should not be given to patients with reduced kidney function (creatinine clearance below 60ml/min). As ddI is also partly eliminated by the kidneys, it is recommended that it is taken in a separate dose from tenofovir, with tenofovir taken at least two hours before or one hour after ddI.
The Portland case concerned a 49 year old man who was first diagnosed with AIDS in 1987. His CD4 cell count had been consistently below 100 cells/mm3 since 1995 and he had a history of severe ill health including anaemia, asthma, peripheral neuropathy and lymphoma, which was in remission. Mild renal insufficiency had been diagnosed in 1996.
Seven weeks before his emergency admission to hospital the man’s viral load was 1100 copies/ml and CD cell count was 35 cells/mm3. His HAART regimen was therefore switched from ddI 400mg once daily, efavirenz, saquinavir and ritonavir to ddI 400mg once daily, tenofovir 300mg once daily, amprenavir and ritonavir.
Doctors were monitoring the patient’s renal insufficiency. In the year before his emergency admission, and in the previous year his creatinine level had ranged from 1.9 to 2.8mg/dl, and was 2.3mg/dl just before he started tenofovir therapy (with an estimated creatinine clearance of 41ml/min). ddI had been prescribed for over three years, and the patient had been taking the enteric-coated version of the drug for several months. However, ddI was dosed at 400mg a day, higher than the recommended 200mg a day for people with a creatinine clearance of 3—59ml/min, and this could have led to increased concentrations of ddI.
The patient and doctor discussed the potential for his new regimen to cause kidney or pancreas toxicities, but it was decided to go ahead in the belief that the new regimen would have greater benefit. Because of the potential for interaction between ddI and tenofovir, the man was told to take the drugs twelve hours apart.
At a follow-up appointment two weeks later, the man’s creatine level was 2.0mg/dl, suggesting that the new combination was being well tolerated. However, there was swelling of the lower legs and feet, which was thought to be related to hydrocortisone therapy for renal insufficiency and low albumin levels, and twice daily 40mg furosemide was prescribed to treat it.
Two weeks later the patient returned with persistent swelling of the lower extremities. Doctors changed furosemide to bumetanide (2mg twice a day). The man also reported an increase in pain in his lower legs and feet, which doctors attributed to the swelling, but subsequently believe was a worsening of the patient’s peripheral neuropathy. However, the swelling responded to the change of drugs.
The man attended the hospital’s emergency department two weeks later reporting a four-day history of progressive fatigue, urine retention, muscle pain, and worsening peripheral neuropathy. The man had low blood pressure (90/50mm Hg), and a creatinine level of 7.6mg/dl, and had blood and protein in his urine. Anti-HIV therapy was stopped.
On admission to intensive care his lactic acid level was 5.5mM and increased to 16.7mM despite therapy to lower it. No evidence of infection was found and doctors concluded that the man’s high lactic levels were due to drug toxicity.
Despite further treatment to lower lactic acid levels, the man’s condition continued to worsen and intensive care was withdrawn in accordance with the patient’s wish that he did not receive prolonged aggressive therapy. He subsequently died.
The man’s doctors attributed the lactic acidosis to a small increase in ddI concentration which caused mitochondrial toxicity. When ddI and tenofovir are administered together, ddI levels increase by up to 44%. The twelve-hour interval between ddI and tenofovir dosing may not have been enough, given the patient’s history of reduced kidney function. Recent research suggests that in healthy volunteers with normal kidney function, a ddI dose reduction to 250mg when taken alongside tenofovir (with or without food) produces similar ddI levels to those seen when ddI is dosed alone.
The Portland doctors believe that worsening renal insufficiency caused an accumulation of both tenofovir and ddI. “The increased tenofovir levels likely increased the already high levels of [ddI], which, in turn led to mitochondrial toxicity, as manifested by lactic acidosis.” At some point the level of tenofovir could have been high enough to cause further kidney toxicity.
”In conclusion, this case suggests that the administration of tenofovir and, particularly, the coadministration of [ddI] should be undertaken with caution in patients with renal insufficiency, even if this seems to be mild and stable.”
Further information on this website
Tenofovir - Overview
ddI - Overview
Lactic acidosis - Overview
First report of tenofovir kidney toxicity - News story
Additional reports of tenofovir kidney toxicity - News story
Case report of kidney lesions in HIV-positive man treated with tenofovir - News story
The kidneys - Factsheet
Murphy MD et al. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clinical Infectious Diseases, 36 (on-line edition), 2003.