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Risk factors for CD4 lymphopenia in patients treated with a tenofovir/didanosine high dose-containing highly active antiretroviral therapy regimen  
  AIDS: Volume 19(10) 1 July 2005
Lacombe, Karinea,b,c; Pacanowski, Jérômea,c; Meynard, Jean-Luca; Trylesinski, Aldod; Girard, Pierre-Mariea,c
aAssistance Publique, Hôpitaux de Paris, Hôpital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, Paris F-75012, France bINSERM, Unité de Recherche en Épidémiologie Systèmes d'Information et Modélisation (U707), Paris F-75012, France cUniversité Pierre et Marie Curie, Faculté de Médecine Pierre et Marie Curie, Paris F-75012, France dGilead Sciences, 100 Avenue de Suffren, Paris F-75015, France.
In this study, the dynamics of CD4 cell depletion during tenofovir/didanosine co-administration were analysed. Ninety-five HIV-positive patients were followed for 562 days, and 37 lost at least 50 CD4 cells, with a median delay of 274 days. Cox analysis showed that the CD4 cell decrease was associated with a duration of treatment by didanosine of more than 853 days and a didanosine dose of more than 5.50 mg/kg.
Concerns have recently been raised about the efficacy of the widely prescribed once-daily tenofovir/didanosine-containing regimen [1]. Some case reports have noted an increase in lactic acidosis and the incidence of pancreatitis in patients treated with tenofovir/didanosine [2,3], and CD4 cell lymphopenia has been reported in patients with an undetectable viral load [4]. However, the dynamics and risk factors of the appearance of CD4 cells have not been documented so far. We conducted an analysis aimed at characterizing CD4 cell dynamics in a cohort of French patients treated with tenofovir/didanosine-containing highly active antiretroviral therapy (HAART).
The study took place in a clinic with 2500 HIV-infected patients. The baseline inclusion criteria were: tenofovir/didanosine-containing HAART prescribed for at least 3 months between October 2002 and September 2004, with a didanosine dosage adapted only to weight, i.e. patients weighing less than 60 kg and 60 kg and over were prescribed the 250 mg/day or the 400 mg/day dose of didanosine, respectively, whatever the previous duration of didanosine. Final analysis was performed in patients achieving a virological response defined by an HIV-RNA load of less than 1000 copies/ml, with CD4 cell counts regularly measured during follow-up and unchanged didanosine dosage. The main judgement criteria were the lowest level of CD4 cell counts achieved by virological responders during follow-up.
HIV immunological and virological status and biochemical data were determined prospectively. The dynamics of the CD4 cell evolution was analysed using methods of survival analysis. Continuous variables were expressed with their medians and 25-75% percentiles, or means and standard deviation (SD). Kaplan-Meier analysis with the log rank test compared groups of patients according to variables likely to influence the CD4 cell count. A Cox proportional hazard model was used to determine the adjusted odds ratios (OR) and 95% confidence intervals (CI) of factors associated with the CD4 cell evolution.
The study population consisted of 95 patients (64 men) aged 40.7 years (range 36.2-48.2). Durations of HIV infection and former antiretroviral treatment were 10.0 years (range 6.2-13.3) and 5.7 years (range 4.0-7.4), respectively, and 21% of the patients had a history of an AIDS-defining event.
Protease inhibitors prescribed in 51 patients were boosted with ritonavir. In 48 and 47 patients, didanosine was prescribed at a dosage of 250 and 400 mg/day, respectively, for a total duration of 853 days (range 91-3504). Overall, the didanosine dose according to the weight of the patients was 4.76 mg/kg (range 3.91-5.80). The dose of didanosine per kg received by patients treated with a 400 mg a day dose was higher than in patients treated with a 250 mg a day dose (5.64 mg/kg, SD 0.71 versus 3.98 mg/kg, SD 0.64, P < 0.0001). All patients received the standard dosage of tenofovir (300 mg/day) and the duration of the combination was 17.4 months (range 10.2-22.9).
The number of blood tests and clinical visits during follow-up was 14 (range 5-15). Before the start of the combination, the HIV viral load was 3.44 log copies/ml (range 1.70-4.19), with a CD4 cell count of 347 cells/mm3 (range 221-492). The viral load reached a level of less than 1000 copies/ml in 63.5 days (range 1-651).
During the study period, 15 patients stopped taking the combination after a duration of 13.10 months (range 6.7-18.8). The reasons given were: late virological failure after initial virological response (seven), mild biological pancreatitis, neuropathy, nephrotoxicity, depression with efavirenz, hepatotoxicity with ribavirine, lipodystrophy (one each) and an acute decrease in the CD4 cell count (two). Creatinine clearance [5] decreased below 80 ml/min in 20 patients out of the 77 with normal renal function at the beginning of treatment (i.e. creatinine clearance = 103.3 ml/min, range 91.3-116.5). The renal function of 15 patients with a creatinine clearance of less than 80 ml/min before treatment remained stable during follow-up and none stopped the combination. No clinical acute pancreatitis was noted, although two and 10 patients presented with a threefold and twofold increase in amylasaemia, respectively (serum amylasaemia at baseline = 61, range 25-182).
Overall, during follow-up, CD4 cell counts declined by three cells (range -90-+80). Thirty-seven patients (38.9%) with an initial CD4 cell count of 306 cells/mm3 (range 194-458) lost at least 50 CD4 cells (median loss = 122 cells/mm3, range 80-210) with a delay of 274 days. This loss was greater in patients with a creatinine clearance of less than 80 ml/min [-193 cells/mm3 (SD 120.4) versus -108 cells/mm3 (SD 52.9) in patients with normal renal function, P < 0.01]. According to Kaplan-Meier analysis, six variables were positively associated with a risk of CD4 cell loss of more than 50 cells/mm3: a duration of HIV infection greater than 10 years (OR 2.02, 95% CI 1.03-3.99); a duration of treatment by didanosine greater than 853 days (OR 1.99, 95% CI 1.03-3.87); a baseline CD4 cell count less than 347 cells/mm3 (OR 2.15, 95% CI 1.09-4.24); an HIV viral load greater than 3.44 log copies/ml (OR 2.09, 95% CI 1.43-5.89); didanosine dose by weight greater than 5.5 mg/kg (OR 1.76, 95% CI 0.99-3.35); and a creatinine clearance rate less than 80 ml/min (OR 1.88, 95% CI 0.99-3.59). Variables not associated with a loss of CD4 cells were sex, age, history of AIDS-defining events, co-treatment by boosted protease inhibitors, and CD4 cell nadir in HIV history. After adjustment for baseline CD4 cell counts, variables remaining independently associated with a decrease of at least 50 CD4 cells in virologically controlled patients were a duration of treatment by didanosine of more than 853 days (OR 1.99, 95% CI 1.03-3.85) and a didanosine dose of more than 5.50 mg/kg (OR 1.95, 95% CI 1.03-3.85).
This study confirmed the loss of CD4 cells in virologically controlled patients treated with tenofovir/didanosine-containing HAART. The results of CD4 cell dynamics showed that this loss occurs early in the combination history, and more quickly if the didanosine dose is high, the duration of didanosine treatment is long, and renal excretion of didanosine is impaired. The mechanism responsible for CD4 lymphopenia might be an accumulation of didanosine metabolites of toxic nature in CD4 cells, perhaps as a result of the inhibition of the purine nucleoside phosphorylase, an enzyme that normally phosphorylases didanosine, leading to didanosine clearance [6]. The inhibition of such an enzyme by tenofovir and a lack of didanosine renal excretion might lead to didanosine cell accumulation and finally apoptosis. Such a hypothesis warrants the close surveillance of CD4 cell counts and renal function, as well as a decrease in the didanosine dosage when co-administered with tenofovir; a policy that has been implemented in the United States, but not in Europe.
1. Leon A, Martinez E, Mallolas J, Laguno M, Blanco JL, Pumarola T, Gatell JM. Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine. AIDS 2005; 19:213-215.
2. Blanchard JN, Wohlfeiler M, Canas A, King K, Lonergan JT. Pancreatitis with didanosine and tenofovir disoproxil fumarate. Clin Infect Dis 2003; 37:e57-e62.
3. Murphy MD, O'Hearn M, Chou S. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clin Infect Dis 2003; 36:1082-1085.
4. Negredo E, Molto J, Burger D, Viciana P, Ribera E, Paredes R, et al. Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS 2004; 18:459-463.
5. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41.
6. Ray AS, Olson L, Fridland A. Role of purine nucleoside phosphorylase in interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir, or tenofovir. Antimicrob Agents Chemother 2004; 48:1089-1095.
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