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Hepatic toxicity associated with 2'-3' dideoxyinosine in children with AIDS
F Lacaille1, M B Ortigao, M Debré
1Department of Pediatrics, Necker Enfants-Malades Hospital, Paris, France.
Insights
Investigating liver abnormalities in children with AIDS treated with 2'-3' dideoxyinosine (ddI), this study found potential hepatotoxicity. Careful liver function monitoring is recommended during ddI treatment in pediatric patients.
Area of Science:
- Pediatric Hepatology
- Infectious Diseases
- Pharmacology
Background:
- Children with AIDS often receive various medications, including nucleoside analogs like 2 -3 dideoxyinosine (ddI).
- Hepatotoxicity has been documented with ddI and similar drugs in adult populations.
- Potential co-factors for liver disease, such as viral infections and other medications, are common in this patient group.
Purpose of the Study:
- To investigate the occurrence and potential causes of liver abnormalities in pediatric patients with AIDS receiving ddI.
- To assess the role of ddI in the development of hepatic toxicity in this cohort.
- To provide recommendations for monitoring liver function in children treated with ddI.
Main Methods:
- Retrospective analysis of 34 children with AIDS treated with ddI.
- Detailed review of clinical data, laboratory results (including liver enzymes and viral serology), and liver histology.
- Assessment of drug-induced toxicity through withdrawal and rechallenge with ddI in affected patients.
Main Results:
- Six of 34 children (aged 1-6 years) developed liver abnormalities within 2-18 months of ddI treatment.
- Two children experienced fatal fulminant hepatic failure; four showed significant elevations in alkaline phosphatase.
- Drug-induced toxicity was suspected in two patients based on ddI withdrawal and rechallenge, while others showed no adverse effects upon readministration.
- Liver histology revealed extensive hepatic necrosis in fatal cases and varying degrees of inflammation and steatosis in others.
Conclusions:
- ddI may precipitate liver disease in predisposed pediatric patients with AIDS, rather than being directly hepatotoxic.
- Concurrent infections (e.g., adenovirus, hepatitis C virus) and other medications (sulfa drugs, antifungals) were potential contributing factors.
- Close monitoring of liver function is crucial for children receiving ddI therapy.
Abstract:
Among 34 children with AIDS enrolled in a trial with 2'-3' dideoxyinosine (ddI), six (aged 1-6 years) developed liver abnormalities within 2-18 months after institution of ddI. Two children died of fulminant hepatic failure (one had also an adenovirus infection), and four had a striking elevation of alkaline phosphatases (AP: 1120-7000 IU/L). All of them received sulfa drugs and antifungic treatment with ketoconazole or fluconazole. Three had a serology positive for hepatitis C virus. The evolution of liver enzymes following withdrawal and rechallenge with ddI in the children with elevated AP was an indication of drug-induced toxicity in two patients. In both of the others, readministration of ddI did not cause any subsequent problems. Liver histology in the patients with fulminant hepatitis showed an extensive hepatic necrosis. Liver biopsy done in two other patients revealed a mild granulomatous hepatitis in one and nonspecific changes (i.e., steatosis and a mild inflammation) in the other. Hepatic toxicity has been described with ddI and other nucleoside analogs in adult patients. These six children had many potential causes of liver disease. It may be that ddI is not hepatotoxic per se but that it precipitates liver disease in predisposed patients. We recommend that liver functions be carefully monitored when using this drug.