Didanosine, also is known as ddI, is a purine nucleoside analog reverse transcriptase inhibitor (NRTI) used in combination with antiretroviral regiments of anti-HIV therapy. After its uptake into a cell, it works by inhibiting the activity of HIV-1 reverse transcriptase. It is also effective as a monotherapy. In several studies, the use of didanosine delayed progression of diseases in AIDS patients and increased both short- and long-term survival.
Didanosine's primary use is in patients intolerant to zidovudine, abacavir, or tenofovir. The patients with the M184V mutation that are failing lamivudine therapy can switch to didanosine. In patients with the M184V mutation, viral serum levels were significantly lower in comparison to the patients treated with HAART therapy without ddI.
Didanosine therapy in children has shown potent in-vivo antiviral activity and delays in disease progression.
Didanosine is a nucleoside analog that must first undergo conversion to its active form dideoxyadenosine-5'-triphosphate (ddATP). ddATP terminates viral DNA growth by inhibiting HIV reverse transcriptase. Multiple clinical trials showed a decrease in plasma HIV RNA levels while increasing CD4+ cell counts in previously untreated patients.
Didanosine is an acid-liable drug with low bioavailability (20-40%). Due to being water-soluble and degraded in the GI tract into inactive hypoxanthine. To increase bioavailability, and remove the need for antacid administration, an encapsulated enteric-coated bead formula was developed. Clinical studies showed a long half-life of an active metabolite, allowing it to be a once-daily dose.
Oral didanosine administration showed an impaired absorption of pH-dependent medications such as itraconazole, dapsone, and ketoconazole. The fetal concentration of didanosine was 20 to 50 percent of the mother's concentration. During the observation, concentration in the cerebrospinal fluid was low. The drug is excreted through the kidneys; thus, dose modification should be a consideration in patients with kidney impairment. Co-administration with ciprofloxacin or tetracycline has shown to impair the absorption of didanosine due to the formation of insoluble chelates.
Didanosine demonstrated as an effective monotherapy in both adults and children; however, to prevent drug resistance, combination therapy is preferred. Due to the reduction of bioavailability by 20 to 25% when administered with food, it is recommended to administer the drug on an empty stomach 30 minutes before ingestion. Dosage, weight depended, is currently 200 mg for patients with body weight over 60 kg orally, twice daily. In adults under 60kg of body weight, the dosage should be reduced to 125 mg, orally, twice daily.
For adults, pediatric powder formulation requires administration with an antacid. The recommended dose, 120 mg twice daily with 12-hour intervals, should be adjusted in a patient with impaired kidney functions.
The combination of zidovudine (200 mg, orally, three times a day) plus didanosine (200 mg, orally, twice daily) should be taken 30 minutes before ingestion.
This combination therapy showed an increase in CD4 cells and a decrease in HIV-1 RNA serum concentrations compared to zidovudine monotherapy. Additionally, delays in AIDS-defining events were significantly prolonged.
This triple therapy consists of nevirapine (200 mg, orally, once daily first two weeks and then 200 mg, orally, twice daily ) plus zidovudine (200 mg, orally, three times a day) plus didanosine (200 mg, orally, twice daily for the patients with body weight over 60 kg).
Patients on triple therapy had an 18% higher mean CD cell count compared to zidovudine and didanosine dual therapy. Severe rashes, however, were observed in patients receiving triple therapy. For these patients, dual therapy is a preferable option.
The combination dosage is as follows: hydroxyurea (500 mg orally, twice daily plus didanosine (200 mg, orally, twice daily). A combination of hydroxyurea and didanosine against HIV-1 has demonstrated the suppression of several resistant-prone strains.
Common Adverse Reactions
Uncommon Severe Adverse Reactions
This contraindication is due to increased mitochondrial toxicity observed in patients with co-administration of didanosine and treatment of Ribavirin, which led to severe metabolic acidosis syndrome.
Didanosine co-administration has shown correlations with hepatoxicity, metabolic acidosis, and peripheral neuropathy.
Co-administration increased systemic exposure to didanosine by up to 300%.
Didanosine use has shown correlations with the development of transplacental oncogenicity in children exposed to the drug in-utero.
During treatment, all patients require monitoring for elevated pancreatic enzyme levels. If signs of drug-induced pancreatitis are present, the clinician should discontinue didanosine. Patients with advanced HIV infections are at an increased risk of developing pancreatitis and should not be placed on didanosine if they have a diagnosis of pancreatitis. Lipase and isoamylase tests have demonstrated to be the most cost-saving and effective method of pancreatic damage in HIV patients.
HIV- infected patients have an increased chance of developing acute kidney injuries, caused by both HIV-dependent and anti-retroviral administration. Patients with signs of lactic acidosis, especially with preexisting renal insufficiency, should be monitored with a high degree of suspicion. For patients with a low risk of kidney disease progression, an annual screen with eGFR, urinalysis, blood pressure, and lipid/glucose levels is recommended. Levels of eGFR in such patients should have monitoring for declines. For patients with an intermediate risk of kidney disease progression, the same tests, with considerations for a renal ultrasound, should be performed every six months. In a case of high risk for kidney disease progression, the patient should have all previously mentioned screenings performed every three months, including a renal ultrasound.
Didanosine, a concentration-dependent drug at high doses, has been shown to inhibit the proliferation of bone marrow progenitor cells. Its myelosuppressive effect is reversible by the administration of erythropoietin. Co-administration with tenofovir has correlations with didanosine overdose and hyperglycemia in underweight patients. This finding suggests taking caution when administering these drugs together to prevent serious complications, such as a diabetic coma.
Mitochondrial toxicity, induced by the inhibition of mitochondrial DNA polymerase due to ddI, can cause severe metabolic dysfunctions that are usually associated with inherited mitochondrial disease, most commonly presented as hepatic steatosis, lactic acidosis, and nephrotoxicity.
Intra-ocular toxicity, which presented as peripheral chorioretinal atrophy from ddI administration, has been reported in children under age 2.
The World Health Organization (WHO), 2015 guidelines recommended initiation antiretroviral therapy in all HIV positive patients. Studies have shown that early administration of antiretroviral therapy significantly decreased cost as well as adverse patient outcomes.
When managing patients with existing comorbidities, it is essential to communicate with other clinicians for assistance. Collaboration between health care providers can decreases instances of developing life-threatening events. Due to the increased toxicity of didanosine, it is important to educate patients about signs of potentially life-threatening conditions associated with drug administration.
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