Protease inhibitors, particular lopinavir and ritonavir can interact with the nucleotide analogue tenofovir resulting in kidney toxicity, warn French investigators writing in the on-line edition of the December 15th issue of Clinical Infectious Diseases (now available online).
The French physicians report the case of a 34 year old gay man who was admitted to hospital in May 2003 with a five week history of fatigue, dehydration, weight loss, painful neuropathy in the lower limbs, polyuria (the passage of a large volume of urine) – and polydipsia (excessive or abnormal thirst). The man had high blood pressure and a rapid heart rate. No evidence of infectious disease was found. His CD4 cell count at hospitalisation was 87 cells/mm3 and his viral load 13,000 copies/mL.
At the time of admission, the patient was taking an anti-HIV treatment regimen consisting of 3TC, ddI, lopinavir/ritonavir, and tenofovir.
Doctors diagnosed Fanconi syndrome, a kidney condition which has been previously reported in patients treated with tenofovir. All antiretroviral therapy was stopped, and the man’s condition improved after 17 days of hydration therapy, multivitamins and amlodipine (a treatment for blood pressure), and he was discharged from hospital, but was not restarted on HAART.
Therapeutic drug monitoring performed two weeks before the man’s admission to hospital showed plasma concentrations of tenofovir of 0.412/mg/L (expected value, 0.12mg/L) and a plasma concentration of ddI of 0.444mg/L (expected value, 0.12mg/L). Before the patient had started taking tenofovir, his ddI plasma level had been 0.05mg/L, increasing to 0.23mg/L after eight months of tenofovir therapy. Plasma levels of lopinavir remained ~9mg/L.
The investigators comment that their patient’s clinical and biological characteristics were consistent with Fanconi syndrome and nephrogenic diabetes insipidus. “This case can be added to the five cases that were recently attributed to tenofovir therapy”, write the authors.
Patients in all six cases used ritonavir and the investigators suggest that ritonavir can increase proximal tubular concentrations of tenofovir in the kidneys, leading to toxicity.
Investigators note that their patient, and two of the others in whom Fanconi syndrome has been reported in association with tenofovir, was also taking ddI. Plasma concentrations of ddI can be increased by between 30%-60% when the drug is used with tenofovir, explaining this patient’s neuropathy.
The extraordinary increase in tenofovir levels in this patient may be connected with ritonavir, the researchers suggest.
Tenofovir is taken up into the proximal tubular cells of the kidneys by human organic anion transporter-1 (OAT-1), and is removed and secreted into the urine by multidrug resistance protein MRP-2.
Ritonavir is a potent inhibitor of p-glycoprotein and of MRP-2-mediated transport, both of which might lead to increased proximal tubular concentrations of tenofovir by reducing its efflux from the kidneys. Substances that might increase OAT-1 activity should be treated with suspicion whenever combined with tenofovir and/or ddI, the authors suggest, highlighting another case report of ddI-associated proximal tubulopathy in which aciclovir was dosed alongside ddI (aciclovir is a substrate for OAT-1).
The investigators call for further examination of interactions between lopinavir, ritonavir, and other protease inhibitors and tenofovir and conclude, “it is highly recommended that patients receiving tenofovir and protease inhibitors be monitored for renal impairment”.
Further information on this website
First report of tenofovir kidney toxicity - news story
Additional case reports of tenofovir kidney toxicity - news story
HIV-positive man dies of kidney failure and lactic acidosis due to tenofovir/ddI interaction - news story
Case report of kidney lesions in HIV-positive man treated with tenofovir - news story
Tenofovir - overview
The kidneys - factsheet
Rollot F et al. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immune deficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clinical Infectious Diseases 37 (on-line edition), 2003.