Tenofovir + ddI: A Combination to Avoid
Tenofovir + ddI: A Combination to Avoid
Tenofovir + ddI has become a commonly prescribed regimen, but evidence is mounting that it may be problematic. Eugenia Negredo and colleagues previously reported that tenofovir combined with full-dose ddI could lead to impaired CD4-cell response despite virologic suppression ( AIDS 2004; 18:459). Subsequent pharmacokinetic data showed that tenofovir increases ddI exposure, leading to the recommendation that ddI doses should be reduced when combined with tenofovir. Now, Negredo's new research, summarized at ICAAC, suggests that such dose reductions may not fully restore immune response. After patients had their ddI dose reduced to 250 mg daily, CD4-cell counts improved modestly in those who had experienced a CD4-cell count decline; however, they did not recover to the levels seen in patients who had not experienced a decline.
At the same conference, Vincent Soriano reported data for Barrios and colleagues on a large retrospective analysis of about 400 patients who received tenofovir, ddI, or both as part of a PI-sparing regimen. Despite virologic suppression, CD4-cell counts were lower than baseline among treatment-experienced patients after 1 year of receiving tenofovir + ddI as part of an NNRTI regimen (decline, 27 cells/mm) - and higher than baseline among those who received only ddI (increase, 51 cells/mm) or tenofovir (increase, 73 cells/mm) with their NNRTI regimens. Soriano postulated that the underlying mechanism for the poor CD4-cell count response with tenofovir + ddI might be related to both drugs being adenosine analogues: their metabolites may be competing for the physiologic adenosine pool, thereby limiting cell reproduction.
Although both of these studies demonstrated virologic suppression with tenofovir + ddI, Daniel Podzamczer suggested at this summer's 13th International HIV Drug Resistance Workshop that the combination might actually impair virologic response when used as part of an initial efavirenz-containing regimen ( Antivir Ther 2004; 9:S172). A randomized trial by Graeme Moyle and colleagues supports these findings. As described in a poster presentation at ICAAC, patients in this trial were assigned to receive ddI + efavirenz with tenofovir or 3TC. However, the study was stopped early because higher rates of virologic failure were observed in the tenofovir group (5/29) than the 3TC group (0/23) at 12 weeks. All of the patients who failed had viral loads >100,000 copies/mL.
Based on the Podzamczer study, as well as a retrospective review that demonstrated virologic failure in 7 of 14 patients who received tenofovir + ddI with efavirenz or nevirapine, Bristol-Myers Squibb issued a "Dear Health Care Provider" letter, advising caution when prescribing tenofovir + ddI with an NNRTI. Shortly after ICAAC, at the 7th International Congress on Drug Therapy in HIV Infection, Negredo presented data for Clotet and colleagues from the TORO studies, further demonstrating impaired CD4-cell responses in patients treated with tenofovir + ddI compared with those receiving either drug alone. Given the data on CD4-cell count response and virologic failure in treatment-naive patients, clinicians might consider a conservative approach of using tenofovir + ddI only when alternatives do not exist. - Paul E. Sax, MD
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Tenofovir + ddI has become a commonly prescribed regimen, but evidence is mounting that it may be problematic. Eugenia Negredo and colleagues previously reported that tenofovir combined with full-dose ddI could lead to impaired CD4-cell response despite virologic suppression ( AIDS 2004; 18:459). Subsequent pharmacokinetic data showed that tenofovir increases ddI exposure, leading to the recommendation that ddI doses should be reduced when combined with tenofovir. Now, Negredo's new research, summarized at ICAAC, suggests that such dose reductions may not fully restore immune response. After patients had their ddI dose reduced to 250 mg daily, CD4-cell counts improved modestly in those who had experienced a CD4-cell count decline; however, they did not recover to the levels seen in patients who had not experienced a decline.
At the same conference, Vincent Soriano reported data for Barrios and colleagues on a large retrospective analysis of about 400 patients who received tenofovir, ddI, or both as part of a PI-sparing regimen. Despite virologic suppression, CD4-cell counts were lower than baseline among treatment-experienced patients after 1 year of receiving tenofovir + ddI as part of an NNRTI regimen (decline, 27 cells/mm) - and higher than baseline among those who received only ddI (increase, 51 cells/mm) or tenofovir (increase, 73 cells/mm) with their NNRTI regimens. Soriano postulated that the underlying mechanism for the poor CD4-cell count response with tenofovir + ddI might be related to both drugs being adenosine analogues: their metabolites may be competing for the physiologic adenosine pool, thereby limiting cell reproduction.
Although both of these studies demonstrated virologic suppression with tenofovir + ddI, Daniel Podzamczer suggested at this summer's 13th International HIV Drug Resistance Workshop that the combination might actually impair virologic response when used as part of an initial efavirenz-containing regimen ( Antivir Ther 2004; 9:S172). A randomized trial by Graeme Moyle and colleagues supports these findings. As described in a poster presentation at ICAAC, patients in this trial were assigned to receive ddI + efavirenz with tenofovir or 3TC. However, the study was stopped early because higher rates of virologic failure were observed in the tenofovir group (5/29) than the 3TC group (0/23) at 12 weeks. All of the patients who failed had viral loads >100,000 copies/mL.
Based on the Podzamczer study, as well as a retrospective review that demonstrated virologic failure in 7 of 14 patients who received tenofovir + ddI with efavirenz or nevirapine, Bristol-Myers Squibb issued a "Dear Health Care Provider" letter, advising caution when prescribing tenofovir + ddI with an NNRTI. Shortly after ICAAC, at the 7th International Congress on Drug Therapy in HIV Infection, Negredo presented data for Clotet and colleagues from the TORO studies, further demonstrating impaired CD4-cell responses in patients treated with tenofovir + ddI compared with those receiving either drug alone. Given the data on CD4-cell count response and virologic failure in treatment-naive patients, clinicians might consider a conservative approach of using tenofovir + ddI only when alternatives do not exist. - Paul E. Sax, MD
Click here for AIDS Clinical Care subscription information.