Treatment of HIV infection---Didanosine

Didanosine (2u,3u-dideoxyinosine, ddI) is a synthetic purine nucleoside analog that is active against HIV-1 and HIV-2, including strains of HIV that are resistant to zidovudine and lamivudine. It was the second drug licensed for the treatment of HIV infection and was initially used as monotherapy, but is now always used as part of combination antiretroviral therapy. The drug is marketed by Bristol-Myers Squibb under the trade names Videxs and Videxs EC (Bristol-Myers Squibb, 2007). The recent availability of didanosine as enteric-coated capsules (Videx EC) has greatly improved the gastrointestinal tolerability of the drug. The concentration can be expressed as mM or in mg/ml (1 mg/ml is approximately equivalent to 5 mM).

TOXICITY

Adverse reactions associated with the administration of didanosine have been well known since the initial clinical trials with the drug. The most serious toxicity of didanosine is pancreatitis, which may be fatal. Other important toxicities include lactic acidosis, severe hepatomegaly with steatosis, retinal changes with optic neuritis and peripheral neuropathy. The patient information leaflet includes a warning about didanosine’s most dangerous adverse reactions. 

Abnormal fat redistribution or lipodystrophy has also become a common long-term adverse reaction to almost all combinations of antiretroviral drugs. Mitochondrial toxicity is the most likely mechanism explaining the adverse reactions to didanosine. Mitochondrial toxicity is a common feature among nucleoside reverse transcriptase inhibitors such as zidovudine, stavudine, abacavir, lamivudine, and didanosine, although the degree of mitochondrial damage varies from one drug to another. Inhibition of the cellular DNA polymerasegamma by the nucleoside analogs impairs mitochondrial DNA synthesis, leading to mitochondrial dysfunction and the subsequent clinical manifestations. Target organs for didanosine mitochondrial toxicity are the pancreas, the liver, peripheral nerves, and probably also the fat tissue . 

CLINICAL USES

Didanosine has been in use since the early days of antiretroviral treatment and has a very different toxicity profile and resistance profile to zidovudine. Owing to toxicity, it should not be administered with stavudine except in rare circumstances. Development of a once-daily enteric-coated formulation has minimized one of the main side-effects, diarrhea, and has allowed more convenient administration. Didanosine plays an important role in many second-line regimens, including those tailored for use in resource-limited settings, but is no longer recommended as a first-line antiretroviral drug.

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