Didanosine, which is a synthetic
nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of
HIV-1 reverse transcriptase by competing with the natural substrate. Currently,
didanosine is mainly provided as an enteric-coated
capsule. In vitro, the molecule is active against laboratory strains and clinical isolates of HIV-1 in resting and activated T cells and monocyte/macrophages.
Didanosine may select for resistance mutations that may render the
drug inactive against the virus; L74V and K65R remain as the main
didanosine-related mutations. In vitro, phenotypic susceptibility to
didanosine was decreased beyond a defined fold change clinical cut-off (1.7), and it is considered that genotypic resistance exists when five
thymidine-associated mutations or four plus M184V are present. In vivo, clinical studies have shown that
didanosine retains significant
antiviral activity in patients who have up to five
nucleoside analogue mutations at baseline.
Didanosine is useful in patients with no previous
therapy, as well as in experienced patients in whom one or more antiretroviral regimens has failed.Enteric-coated
didanosine is taken once daily, its co-administration with food has been recently evaluated and a reduction of the efficacy of the antiretroviral treatment was not observed. Administered with
lamivudine (or
emtricitabine), it can be considered a good alternative for use in the
nucleoside analogue backbone included in combination
therapies for antiretroviral-naive patients.
Didanosine could be used in initial treatments for patients intolerant of
zidovudine,
abacavir or
tenofovir. It can be included in once-daily combination regimens, which are more convenient and patient friendly.Prospective, observational and open-label studies, as well as clinical trials (with durations between 24 and 96 weeks), have demonstrated the safety and efficacy of
didanosine plus
lamivudine (or
emtricitabine) plus
efavirenz (or
nevirapine) in previously untreated HIV-1-infected patients. The administration of
didanosine to treatment-experienced patients has been evaluated in two different contexts: patients in whom previous
therapies have failed (rescue
therapy) and those with controlled viraemia who are switched to a
didanosine-containing regimen for simplification.Adverse events associated with the administration of
didanosine have been well known since the initial clinical trials with the
drug. Gastrointestinal intolerance,
peripheral neuropathy and hyperamylasaemia/
pancreatitis were the most frequently reported. In the
highly active antiretroviral therapy (
HAART) era, the rate of adverse events has decreased. The tolerability of
didanosine has been clearly improved with the development of the enteric-coated
capsule. Severe manifestations of mitochondrial toxicity, including
lactic acidosis and abnormal fat distribution, are rare complications, and occur most frequently when
didanosine is used in combination with
stavudine.