February 7, 2001
Pancreatitis has been associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs), especially didanosine (Videx, ddI). The cause of this toxicity is unknown but it is suspected that it is related to mitochondrial toxicity. Due to the increased rate of severe pancreatitis or deaths that have occurred in some studies that combined ddI and hydroxyurea (Hydrea, HU), there is concern about the use of hydroxyurea to boost the intracellular effectiveness of ddI.
This study examined the incidence of pancreatitis over eight years, from January 1992 to August 2000, in an HIV clinic. Pancreatitis was defined as the patient having a clinical history indicating that diagnosis and having either supporting biochemical evidence (elevated amylase and lipase), or radiographic evidence, post-mortem, or hemorrhagic pancreatitis.
This retrospective study evaluated the records of 2,613 patients and found 33 cases of pancreatitis, including one fatal case in a patient treated with ddI/stavudine (d4T)/HU. The crude rate of pancreatitis for each antiretroviral was: 0.8 cases/100 person-years (PY) on therapy with ddI; 1.0 case/PY for d4T; 1.5 cases/PY for ddI/d4T; 6.0 cases/PY for ddI/HU; 2.2 cases/PY for ddI/d4T/HU; and 0.15 cases/PY for zidovudine (AZT). Compared to ddI alone, and adjusted for CD4+ cell count and other variables, a significant relative risk of 8.6 was found for ddI/HU used in combination, whereas the relative risks for d4T and the other combinations were not significant. The other significant risk factors for pancreatitis in this study were CD4+ cell count <200 cells/mL, female gender, and a history of pancreatitis. Protease inhibitors, non-nucleoside reverse transcriptase inhibitors, age, race, and illicit drug use or alcohol use were not significantly associated with pancreatitis.
This study indicates that ddI and HU combinations have a significantly higher rate of pancreatitis than other drugs or drug combinations and therefore they probably should not be used together. Clinicians have been aware of these problems for several years and have already accepted and adopted this advice. Moreover, given the high rate of pancreatitis with the "D" drugs, it may be advisable to avoid their use in patients with a history of pancreatitis or who appear, based upon risk factors, to be highly susceptible to pancreatitis.