Tung_2004_BHIVA

							         The Durability of Tenofovir (TFV) and Didanosine (ddI) When
             Dosed Together Using Low Dose Didanosine 250mg.
                                                                             Tung M, Mandalia S, Bower M, Nelson MR, Gazzard BG
                                                                             St. Stephens Centre, Chelsea and Westminster Hospital
                                                                                    369 Fulham Road, London SW10 9NH, UK.




                                         INTRODUCTION                                                             TOLERABILTY AND SIDE EFFECTS
Tenofovir (TFV) and Didanosine (ddI) are potent once daily reverse transcriptase inhibitors, effective
against HIV-1 infection. Pharmacokinetic studies have demonstrated that when TFV is co-administered               Figure 3
with ddI 400mg, ddI plasma concentrations are increased by up to 60%. These results led to concerns
                                                                                                                                                      Table of treatment discontinuations
regarding side effects and toxicity. Current recommendations suggest reducing ddI dosage to 250mg
when used in combination with TFV, to minimise this interaction.
                                                                                                                                    Reason for                TFV + ddI 250            TFV + ddI 400
                                                                                                                                  discontinuation                N= 33                    N= 45
                                            OBJECTIVES
                                                                                                                                      Toxicity                      2                         12
To look at the virological efficacy and clinical tolerability of highly active antiretroviral therapy (HAART)
combinations containing Tenofovir and Didanosine 250mg or Didanosine 400mg.                                                     Virological Failure                 2                         3
                                                                                                                                 Patient Request                    0                         1
                                                                                                                                  Starting Hep C                    1                         0
                                              METHODS                                                                               treatment


A retrospective analysis was performed of patients who commenced an antiviral regimen containing TFV              The majority of treatment discontinuations were due to toxicity and side effects – probably relating to
with either ddI 250mg or ddI 400mg for the first time. All patients were previously antiviral experienced,        increased mitochondrial toxicity.
with a mean number of 4 previous HAART regimens.
78 patients, with a viral load less than 50 copies/ml, receiving an antiviral regimen containing TFV and ddI
were identified. 33 Individuals were taking TFV and ddI 250mg; taken simultaneously with a light meal. 45         Figure 4                       Table of toxicity related discontinuations
individuals were taking TFV and ddI 400mg; taken separately at least 2 hours apart and in a fasted state.
                                                                                                                                      Toxicity                TFV + ddI 250             TFV + ddI 400
                                               RESULTS                                                                          Pancreatic toxicity                  0                        3
VIROLOGICAL + IMMUNOLOGICAL SUCCESS
                                                                                                                                  Lactic Acidosis                    0                        1

33 patients were taking TFV and ddI 250mg and the median duration of treatment was 356 days (range                               Hyperlactataemia                    0                        2
302 – 434 days). This compares to 45 patients taking TFV and ddI 400mg for a median time of 215 days
(range 127 – 308 days).                                                                                                       Peripheral neuropathy                  1                        2


We analysed the time from the start of the study to treatment failure; defined as either virological failure or                   GI side effects                    0                        4
switch of therapy off TFV or ddI due to toxicity. The survival distribution curve demonstrates that time to
treatment failure is significantly slower in individuals receiving TFV and ddI 250mg, p value = 0.005.                         Hypophosphataemia                     1                        0




                                                                                                                  Looking more closely at the toxicity related discontinuations, lactic acidosis and hyperlactataemia
Figure 1                                                                                                          related to mitochondrial toxicity, and pancreatitis were the common causes identified as shown in
                                                                                                                  table 4. There have been documented reports of nephrotoxicity associated with the use of TNF. So
                                                                                                                  far in this cohort there have been no cases of TFV related renal toxicity.




                                                                                                                                                            DISCUSSION

                                                                                                                     • Time from virological suppression to treatment failure is significantly slower in patients receiving
                                                                                                                     TFV and ddI 250mg

                                                                                                                     • There were fewer toxicity related discontinuations in patients taking TFV + ddI 250


                                                                                                                                                             CONCLUSION
Looking at median CD4 count change over 6 months, there was no significant difference between the two
groups.
                                                                                                                     • Our clinical cohort has shown that    using TFV with ddI 250mg is a safe, well tolerated and
                                                                                                                     effective combination.
Figure 2                       Table of median CD4 count (cells/mm³)

                                                TFV + ddI 250mg             TFV + ddI 400mg

                       Baseline                       328                         373
                   Median CD4 count

                    6/12 treatment                    320                         359
                   Median CD4 count