Abstract 617 - Fatal Hepatotoxicity Associated with Combination Hydroxyurea and Nucleoside Reverse Transcriptase Inhibitors (NRTIs): Cases From the FDA Adverse Event Reporting System (AERS).

617 Fatal Hepatotoxicity Associated with Combination Hydroxyurea and Nucleoside Reverse Transcriptase Inhibitors (NRTIs): Cases From the FDA Adverse Event Reporting System (AERS).

D. Boxwell and J. Toerner*.
FDA, Rockville, MD.

Background:Hydroxyurea (HU) used in combination regimens for treatment of HIV, while still investigational, has entered clinical practice. Hepatotoxicity is a labeled event for all NRTIs, yet the risk of hepatotoxicity associated with the use of HU and NRTIs is not well characterized.

Methods:AERS was searched for reports of hepatotoxicity associated with combination HU/NRTI therapy in HIV-infected patients.

Results:34 cases were found of hepatotoxicity associated with the use of any NRTI plus HU, at doses up to 1 gram/day. Hepatic failure, hepatitis, hepatic steatosis, and increased liver function tests were the primary hepatotoxic events. Didanosine (DDI) use was reported in 31 (91%) cases. Of 18 cases reporting DDI/D4T/HU use, 61% were fatal. Of 16 cases reporting other NRTI/HU use, 25% were fatal. Mean time to onset of hepatotoxicity was 11.0 weeks for survivors and 18.4 weeks in fatal cases. Because the percentage of death in DDI/D4T/HU patients was disproportionately high in this small case series, all reports of hepatotoxicity associated with DDI/D4T were evaluated. 93 unduplicated cases of hepatotoxicity associated with DDI/D4T were found in an updated AERS run. Concomitant DDI/D4T/HU use was now reported in 20/93 cases; 55% of these cases were fatal. Of 73 cases reporting DDI/D4T use without concomitant HU, 34% were fatal. Hepatic failure (45%) and hepatic necrosis (27%) were the major liver events reported in the fatal DDI/D4T/HU cases. Hepatic failure (48%) and lactic acidosis plus hepatic steatosis (36%) were more common in patients who died but were not taking HU.

Conclusions:We conclude that combination HU/NRTI use may enhance the risk of death due to hepatotoxicity. Voluntary reporting systems clearly have limitations; however, HU's potential to enhance intracellular incorporation of NRTIs, combined with liver toxicity associated with NRTIs, helps support this conclusion. DDI/ D4T/HU combination may further enhance the risk of fatal outcome. Shorter time to onset of hepatotoxicity in patients who lived may reflect earlier recognition of hepatotoxicity. Patients taking HU and NRTIs, in particular DDI/D4T, should be aggressively monitored for hepatotoxicity.