Indications

Didanosine, also known as ddI, is a purine nucleoside analog reverse transcriptase inhibitor (NRTI) that was used in combination with antiretroviral regimens of anti-HIV therapy. It was removed from the market due to adverse effects and drug interactions. The article is for historical purposes only. After its uptake into a cell, it works by inhibiting the activity of HIV-1 reverse transcriptase. It is also effective as a monotherapy.[1] In several studies, the use of didanosine delayed the progression of diseases in AIDS patients and increased both short- and long-term survival.[2]

Didanosine's primary use is in patients intolerant to zidovudine, abacavir, or tenofovir. Patients with the M184V mutation that are failing lamivudine therapy can switch to didanosine.[3] In patients with the M184V mutation, viral serum levels were significantly lower than those treated with highly-active retroviral therapy (HAART) without ddI.[4]

Didanosine therapy in children has shown potent in-vivo antiviral activity and delays in disease progression.[5] 

Mechanism of Action

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.[5]

Didanosine is an acid-liable drug with low bioavailability (20 to 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.[6] Clinical studies showed a long half-life of an active metabolite, allowing it to be a once-daily dose.[7] 

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.[5] The drug is excreted through the kidneys; thus, dose modification should be considered in patients with kidney impairment. Co-administration with ciprofloxacin or tetracycline has been shown to impair the absorption of didanosine due to the formation of insoluble chelates.[1]

Administration

Didanosine has been 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.[5]

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.[5][1]

Dual Combination Therapy with Nucleoside Reverse Transcriptase Inhibitor(NRTI)

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.[8][9]

Triple Combination Therapy with Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) and Nucleoside Reverse Transcriptase Inhibitors(NRTI)

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.[10]

 Dual combination with DNA synthesis inhibitors. 

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.[11]

Adverse Effects

Common Adverse Reactions

• Peripheral neuropathy
• Pancreatitis
• Portal hypertension
• Lactic acidosis
• Hepatitis
• Optical neuritis
• Hepatomegaly with steatosis
• Hyperglycemia
• Development of diabetes mellitus 
• Hyperuricemia
• Depression
• Restlessness
• Anxiety

Uncommon Severe Adverse Reactions

• Diarrhea
• Headache
• Nausea
• Rash 
• Vomiting
• Agitation
• Dizziness

Contraindications

Didanosine contraindications include concomitant use with the following drugs:

Ribavirin

• 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.[12]

Stavudine

• Didanosine co-administration has shown correlations with hepatoxicity, metabolic acidosis, and peripheral neuropathy.[13]

Allopurinol

• Co-administration increased systemic exposure to didanosine by up to 300%.[14]

Didanosine is also contraindicated in pregnancy as use has shown correlations with the development of transplacental oncogenicity in children exposed to the drug in-utero.[15]

Monitoring

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.[16] Lipase and isoamylase tests have been demonstrated to be the most cost-saving and effective method of pancreatic damage in HIV patients.[17]

HIV- infected patients have an increased chance of developing acute kidney injuries caused by both HIV-dependent and anti-retroviral administration.[18] Patients with signs of lactic acidosis, especially with preexisting renal insufficiency, should be monitored with a high degree of suspicion.[19] 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, plus consideration for a renal ultrasound, should be performed every six months. In cases with a high risk for kidney disease progression, the patient should have all previously mentioned screenings performed every three months, including a renal ultrasound.[20]

Toxicity

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.[5] 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.[21]   

Mitochondrial toxicity, induced by the inhibition of mitochondrial DNA polymerase due to ddI, can cause severe metabolic dysfunctions usually associated with inherited mitochondrial disease, most commonly presented as hepatic steatosis, lactic acidosis, and nephrotoxicity.[22]

Intra-ocular toxicity, which presented as peripheral chorioretinal atrophy from ddI administration, has been reported in children under age 2.[23]

Enhancing Healthcare Team Outcomes

The World Health Organization (WHO), 2015 guidelines recommended the initiation of 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.[24]

When managing patients with existing comorbidities, it is essential to communicate with other clinicians for assistance, operating as a cohesive interprofessional team. This team includes clinicians (including PAs and NPs), specialists, nursing staff, and pharmacists. Collaboration between health care professionals can decrease 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. These points can be reinforced by clinicians, nursing staff, and pharmacists. Operating as a coordinated interprofessional team will increase the chance for successful outcomes with didanosine and HAART therapy. [Level 5]