Duration of ddI (Videx) therapy and ddI dose are risk factors for the loss of CD4 T-cells in patients with a controlled viral load taking a highly active antiretroviral therapy (HAART) combination including ddI and tenofovir (Viread), according to a French study published in the July 1st edition of AIDS. The investigators believe that the reason could be a build up of toxins in CD4 T-cells caused during the metabolising of ddI.
An increased incidence of lactic acidosis and pancreatitis has been observed in patients taking ddI and tenofovir. Recently European regulatory authorities cautioned doctors against prescribing ddI and tenofovir together, after some studies found virological failure and resistance in individuals taking the two drugs as part of a HAART regimen. These studies involved treatment-naïve individuals taking a non-nucleoside analogue who had high viral loads and low CD4 cell counts.
As the dynamics and risk factors for CD4 cell loss in individuals taking a HAART combination including ddI and tenofovir have not been well studied, French investigators undertook an analysis of 95 patients with controlled viral load treated with the combination between 2002 and 2004.
Individuals were treated with a dose of ddI dependent on body weight, with patients weighing less than 60kg prescribed 250mg a day, and those weighing over 60kg prescribed 400mg per day.
The patients had a median age of 41 years, and the median duration of diagnosed HIV infection was ten years. Antiretroviral therapy had been used for a median of six years and a little over a fifth of patients had been diagnosed with AIDS.
A total of 48 patients received the 250mg daily dose of ddI, the remaining 47 individuals receiving 400mg a day.
Before treatment with the ddI/tenofovir-containing regimen was initiated, the median CD4 cell count was 347 cells/mm3 and median viral load was 2,500 copies/ml. Viral load fell to less than 1,000 copies/ml in a median of 63 days after treatment was started.
During a total of 562 days of follow-up, the median CD4 cell count loss in the cohort was 3 cells/mm3. However, 39% of patients, with an initial median CD4 cell count of 309 cells/mm3 lost 50 cells/mm3 after a median of 274 days of treatment. The loss was greater in patients with a creatinine clearance of less than 80ml/min.
After adjustment for baseline CD4 cell count, the investigators established that the factors independently associated with a loss of 50 or more CD4 cells/mm3 were duration of ddI therapy of 853 days or more and a ddI dose of more than 5.50mg/kg.
“This study confirmed the loss of CD4 cells in virologically controlled patients treated with ddI/tenofovir-containing HAART”, write the investigators.
They add, “the results of CD4 cell dynamics showed that this loss occurs early in the combination history, and more quickly if the ddI dose is high, the duration of ddI is long, and renal excretion of ddI is impaired.”
They speculate that CD4 cell loss could be due to the build up of toxins during the metabolising of ddI, possibly due to the inhibition of the enzyme purine nucleoside phosphorylase which is normally involved in the secretion of ddI. Tenfovoir inhibits this enzyme and the lack of ddI excretion from the kidneys could lead to the accumulation of ddI in the cells and finally cell death.
“Such a hypothesis warrants the close surveillance of CD4 cell counts and renal function, as well as a decrease in ddI dosage when co-administered with tenofovir,” conclude the investigators.
Lacombe K et al. Risk factors for CD4 lymphopenia in patients treated with a tenofovir/didanosine high dose-containing highly active antiretroviral therapy regimen. AIDS 19 (10): 1107 – 1109, 2005.