The combination of ddI (didanosine; Videx) plus d4t (stavudine; Zer (d4T) is no longer recommended as a component of first-line regimens due to toxicity, but it may still be a useful option for treatment-experienced patients.

As reported in the December 15, 2006 Journal of Acquired Immune Deficiency Syndromes, Spanish researchers conducted a retrospective chart review of treatment-experienced patients taking ddI plus d4T, recording the development of adverse events as well as their severity and actions taken.

Results

• A total of 616 patients had been on ddI plus d4T for a median duration of 12 months (interquartile range 5-25 months).

• 213 of these patients (34.6%) had an AIDS diagnosis, 161 (27.4%) had CD4 counts below 200 cells/mm3, and 503 (81.2%) had more than 2 previous treatment failures.

• Adverse events related to ddI plus d4T were recorded for 136 subjects (22.1%), which were mild to moderate in 118 patients (19.1%) and severe in 18 (2.9%).

• The mean times to development of severe and non-severe adverse events were 72 weeks and 52 weeks, respectively.

• The probability of developing severe adverse events was related to nadir (lowest ever) CD4 count, with a higher risk in patients with < 200 cells/mm3.

Conclusion and Discussion

In conclusion, the authors wrote, "Multi-experienced patients treated with combinations including ddI plus d4T frequently develop drug-related toxicity, but these events are rarely severe. Thus, these drugs can still be considered a valid option for salvage regimens."

In their discussion, the researchers said that the low proportion of significant side effects observed in this study may be explained by several factors. The action taken in patients with any adverse events related to ddI and/or d4T - irrespective of severity - was frequently the withdrawal of one or both drugs, or even discontinuation of an entire regimen.

This conservative approach might account for the low proportion of severe adverse events observed. In addition, precautionary warnings for acute pancreatitis with ddI and d4T - as well as for other manifestations of mitochondrial toxicity, such as peripheral neuropathy or lactic acidosis - has no doubt led clinicians to heighten monitoring of side effects.

In this study, there were no documented cases of lactic acidosis. There were 10 cases of mild-to-moderate hyperlactatemia, but lactate levels were carefully monitored and always remained below 5 mmol/L, and the drugs were stopped as soon as lactate levels increased to greater than the upper limit of normal.

Given the retrospective design of this study, the researchers excluded lipoatrophy as a long-term manifestation of mitochondrial toxicity, given that this condition was not recorded in a systematic and consistent manner in the earlier years of the study, since it was neither well recognized nor associated with nucleoside reverse transcriptase inhibitors (NRTIs). The same reasoning could be applied to certain laboratory parameters, such as elevated triglycerides, which have only recently been associated with NRTI toxicity.

Taken together, these results suggest that toxicity rates among patients receiving ddI and d4T together may be lower than perceived, the authors wrote. "Severe toxicity seems to be infrequent even in highly treatment-experienced HIV-infected individuals and in advanced stages of the disease."

"According to our results, fear of toxicity should not preclude using ddI plus d4T in experienced patients, who may benefit from the resistance profile of these drugs and for whom other NRTIs may no longer be available," they concluded.

Department of Infectious Diseases, Hospital Ramón y Cajal, Madrid, Spain.

1/16/07

Reference
B Hernandez, S Moreno, M Perez-Elias, and others. Severity of the Toxicity Associated with Combinations that Include Didanosine Plus Stavudine in HIV-infected Experienced Patients. Journal of Acquired Immune Deficiency Syndromes 43(5): 556-559, December 15, 2006.