Acute pancreatitis associated with severe lactic acidosis in human immunodeficiency virus-infected patients receiving triple therapy

F. Frippiata,*, G. Deruea, F. Hellera, P. Honoreb, M. Moreauc and B. Vandercamc

a Centre Hospitalier de Jolimont-Lobbes, Service de Medecine Interne Generale, Rue Ferrer 159, 7100 Haine-Saint-Paul; b Clinique St Pierre, Service de Reanimation, Avenue Reine Fabiola, 112, 1340 Ottignies; c Cliniques Universitaires Saint-Luc, Service de Medecine Interne Generale, Avenue Hippocrate 10, 1200 Bruxelles, Belgium

Sir,

In a recent issue of the Journal, Allaouchiche et al.1 described a human immunodeficiency virus (HIV)-infected patient receiving treatment with didanosine (ddI), stavudine (d4T) and indinavir who developed acute pancreatitis with severe lactic acidosis. Their conclusion that the adverse effects were attributable to the ddI was based on the failure to identify other potential causes and the observation that they resolved when the triple therapy was discontinued. We believe that either d4T alone or d4T together with ddI might have been equally responsible, since such effects have been observed with nucleoside reverse transcriptase inhibitors (NRTIs) other than ddI, including d4T.2–5 The adverse effects associated with NRTIs are believed to be the result of a unique mechanism related to acquired mitochondrial dysfunction, i.e. the capacity of all currently available NRTIs to inhibit not only viral reverse transcriptase but also human DNA polymerases, including DNA polymerase {gamma}. DNA polymerase {gamma} is the only enzyme in this group involved in mitochondrial DNA replication and has been shown in vitro to be inhibited less by lamivudine (3TC) than by other NRTIs;3 d4T is intermediate between zalcitabine (ddC) and ddI in terms of the potential to cause mitochondrial toxicity.6 We report here a further case of an HIV-positive patient who developed fatal acute pancreatitis and lactic acidosis while receiving d4T, 3TC and indinavir.

A 34 year-old female was admitted to hospital with a 3 day history of abdominal pain, nausea and vomiting. There was no past history of liver or biliary disease, diabetes mellitus or alcohol abuse. Therapy with d4T and 3TC had been initiated 7 months earlier and indinavir was added 2 months later, this regimen resulting in an undetectable viral load and an increase in the CD4+ cell count from 157 x 106 to 259 x 106 cells/L. The drugs were well tolerated, except for mild lipodystrophy, hypercholesterolaemia (7.4 mmol/L) and hypertriglyceridaemia (3.9 mmol/L), but without hyperinsulinaemia. On admission the patient was unconscious and shocked and her abdomen was distended. Ranson's score was 8 and she required intubation and ventilation. There were no abnormalities of the biliary tract on abdominal ultrasound, but computerized tomography showed severe necrotizing pancreatitis. Blood cultures and a sample of cerebrospinal fluid were sterile and common causes of lactic acidosis were excluded. Despite intensive support, including haemofiltration, the patient died on the third day following admission.

Indinavir-induced chylomicronaemia could have accounted for the pancreatitis in this patient. Moderate hyperlipidaemia was detected 1 month before admission and the serum was lactescent at the time of admission, although the serum triglyceride concentrations were not determined on that occasion. None the less, we feel that the d4T was the most likely cause of the patient's presentation. In another patient who developed acute pancreatitis and lactic acidosis, but survived, 3TC and indinavir were reintroduced without any adverse effects.5

Although NRTIs are likely to remain the cornerstone of antiretroviral therapy, the present case illustrates that severe pancreatitis and/or lactic acidosis caused by these drugs can have a rapid and fatal outcome. Clinicians with patients receiving NRTIs should therefore be aware of their potential to produce these complications, which seem to be a class effect.

Notes

J Antimicrob Chemother 2000; 45: 411–412

* Correspondence address. Service de Médecine Interne Générale, Centre Hospitalier Jolimont-Lobbes, Rue Ferrer 159, 7100 Haine Saint-Paul, Belgium. Back

References

1 . Allaouchiche, B., Duflo, F., Cotte, L., Mathon, L. & Chassard, D. (1999). Acute pancreatitis with severe lactic acidosis in an HIV-infected patient on didanosine therapy. Journal of Antimicrobial Chemotherapy 44, 137–8.[Free Full Text]

2 . Lea, A. P. & Faulds, D. (1996). Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection. Drugs 51, 846–64.[ISI][Medline]

3 . Brinkman, K., ter Hofstede, H. J., Burger, D. M., Smeitink, J. A. & Koopmans, P. P. (1998). Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 12, 1735–44.[ISI][Medline]

4 . Brinkman, K., ter Hofstede, H. J., Veerkamp, M. J., Kolke, H. J., Willems, J. L. & Wesserling, P. (1998). Fatal lactic acidosis following HAART containing stavudine (d4T), lamivudine (3TC) and saquinavir. In Program and Abstracts of the Twelfth World AIDS Conference, Geneva, 1998. Abstract 60998.

5 . Lenzo, N. P., Garas, B. A. & French, M. A. (1997). Hepatic steatosis and lactic acidosis associated with stavudine treatment in an HIV patient: a case report. AIDS 11, 1294–6.[ISI][Medline]

6 . Medina, D. J., Tsai, C. H., Hsiung, G. D. & Cheng, Y. C. (1994). Comparison of mitochondrial morphology, mitochondrial DNA content and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides. Antimicrobial Agents and Chemotherapy 38, 1824–8.[Abstract]





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