Interferon alfa Didanosine

Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline levels and increased methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias. 

The use of didanosine 125-200 mg bd plus interferon alfa-2b in AIDS-associated Kaposi s sarcoma has been studied in 68 patients (6). Withdrawal of didanosine was required in cases of peripheral neuropathy, rises in serum amylase activity, and hypertriglyceridemia. 

Multisystem organ dysfunction and lactic acidemia occurred in two of 15 patients with HIV and hepatitis C infections who received interferon alfa, didanosine, and ribavirin (23). Co-administration of didanosine with ribavirin can lead to increased toxicity secondary to raised intracellular concentrations of phosphorylated didanosine (ddA-TP) (24,25). Thus, the evidence suggests that the combination of didanosine plus ribavirin increases the risk of lactic acidosis. 

Interferon alfa does not alter the pharmacokinetics of didanosine or lamivudine to a clinically relevant extent. Interferon alfa and, particularly, interferon beta can cause an increase in the serum levels of zidovudine. HIV-positive patients infected with hepatitis C and treated with interferon alfa and ribavirin may be at special risk of NRTI-associated lactic acidosis. Interleukin-2 appears not to interact significantly with zidovudine. 

In vitro, ribavirin reduced the intracellular activation and antiretroviral activity of stavudine. However, in a study in 5 HIV-positive patients with hepatitis C, ribavirin 800 mg daily had no statistically significant effect on the pharmacokinetics of stavudine (a 45% increase in AUC), and no effect on intracellular activation of stavudine, when compared with similar patients who received placebo. Similarly, no decrease in antiviral activity of stavudine (as assessed by plasma HIV-RNA levels) has been seen when ribavirin was given with interferon for hepatitis C infection in patients with HIV. " Nevertheless, the UK manufacturers of ribavirin continue to recommend that plasma HIV-RNA levels are closely monitored in patients taking ribavirin with stavudine to ensure continued efficacy. In contrast, based on an analysis of data from the adverse event reporting system of the FDA in the US, (see didanosine above), the UK manufacturers of ribavirin consider that concurrent use of stavudine should be avoided to limit the risk of mitochondrial toxicity. The UK manufacturer of stavudine notes that patients co-infected with hepatitis C and treated with interferon alfa and ribavirin may be at increased risk ofNRTI-associated lactic acidosis. Patients at increased risk should be monitored closely. Similarly, the US manufacturer of stavudine states that patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. ... 

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