Overall rates of pancreatitis were similar for patients taking single or dual nucleoside analogue (NRTI) regimens, according to a review of 20 United States clinical trials published in the June 1st edition of the Journal of Acquired Immune Deficiency Syndromes. However, as would now be expected, the combination of ddI/d4T was associated with the highest incidence of pancreatitis of any nucleoside analogue combination, with the HAART regimen of indinavir/ddI/d4T “associated with particularly high rates of pancreatitis, reminiscent of high-dose ddI-monotherapy trials.”
Pancreatitis can be life threatening, symptoms including abdominal pain, nausea, vomiting and elevations in levels of lipase and amylase. Even before HAART became available, the incidence of pancreatitis was higher amongst HIV-positive individuals than the general population, due to coinfections, the use of certain medication, the effect of HIV itself, and AIDS-defining opportunistic infections. In the HAART era the incidence of clinical and laboratory pancreatitis amongst patients taking antiretrovirals was recently calculated to be 0.85 cases per 100 patient years.
US investigators wished to report the incidence of grade 3 or grade 4 clinical and laboratory-defined cases of pancreatitis amongst patients participating in 20 Adult AIDS Clinical Trials Group Studies (AACTG) between 1989 and 1999. These studies involved just under 8,500 patients. All the studies included at least one arm where patients were taking ddI. The analysis was prompted by unexpectedly high levels of severe pancreatitis and death amongst individuals enrolled in the AACTG study into treatment intensification with ddI/d4T with or without hydroxyuraea.
Investigators calculated the rates of clinical pancreatitis and combined clinical/laboratory pancreatitis. There were no uniform criteria used to define clinical pancreatitis across the studies.
The rate of clinical pancreatitis for the combination ddI/AZT was 0.48 per 100 person years, similar to that for ddI monotherapy (0.38 per 100 person years) and AZT monotherapy (0.28 per 100 person years). In addition, the investigators found that when using the clinical/laboratory definition ddI/AZT rates did not differ significantly from ddI monotherapy. However, by using these criteria, a higher rate of clinical/laboratory pancreatitis was seen for ddI/AZT (2.34 per 100 person years) than for AZT monotherapy (0.91 per 100 person years; p
The ddI/hydroxyuraea combination yielded a low rate of clinical pancreatitis, but a higher rate of clinical/laboratory pancreatitis (3.21 per 100 patient years). Alternating AZT and ddI resulted in a “ slightly higher than expected rate” of clinical pancreatitis (1.66 cases per 100 patient years) and clinical/laboratory pancreatitis (3.99 cases per 100 patient years).
Combining AZT and ddI with nevirapine resulted in a significant increase in the rates of both clinical (p
The use of IL-2 did not seem to influence the incidence of pancreatitis.
“Of the combinations of dual NRTIs we studied, ddI/d4T seems to be associated with the highest rates of pancreatitis”, write the investigators, adding that the HAART combination of indinavir/ddI/d4T “seems to be associated with particularly high rates of pancreatitis, reminiscent of high-dose ddI monotherapy trials.”
The investigators caution that “the clinical pancreatitis definition probably underestimates the incidence rate…and the laboratory or chemical pancreatitis definition probably overestimates the incidence rate.”
Commenting on the risks associated with particular drugs and combinations, the investigators suggest that “the frequency of ddI-induced pancreatitis seems to be dose related”, and that their findings support the “black box” warning regarding the use of ddI and d4T in combination. They suggest that the particularly high rates of pancreatitis observed in patients taking indinavir/ddI/d4T could be because this regime “induces particular metabolic and lipid abnormalities at the cellular level that significantly increase the risk of pancreatitis.”
An absence of a consensus of what defines pancreatitis and inconsistencies in the way clinical and laboratory data were collected and analysed is noted by the investigators, who also highlight that they were unable to perform a cross-protocol analysis of incidence and risk factors because the relevant data were not collected in a “uniform and systematic fashion.”
The investigators conclude, “better evidence is needed to determine how much of this pancreatic morbidity is directly attributable to ARV therapy.” They also state that there should be “a pancreatitis case definition that is current and easily implemented”.
Reisler RB et al. Incidence of pancreatitis in HIV-1-infected individuals enrolled in 20 Adult AIDS Clinical Trials Group studies: lessons learned. J Acquir Immune Defic Syndr 39: 159 – 166, 2005.