Didanosine

Didanosine is an oral adenosine analogue and nucleoside reverse transcriptase inhibitor that is now seldom used because of pancreatitis, neuropathy, lactic acidosis and awkward fasting dosing. It is not used in new regimens, but clinicians still meet it in patients on long-established treatment. It carries boxed warnings for pancreatitis, lactic acidosis and hepatomegaly with steatosis, and a fatal-risk warning when combined with stavudine in pregnancy.

Class. Nucleoside reverse transcriptase inhibitor.

Mechanism. Converted to dideoxyadenosine triphosphate, which competes with deoxyadenosine triphosphate and terminates viral DNA synthesis.

Pharmacokinetics. Acid-labile, so given as enteric-coated capsules or buffered formulations. Oral bioavailability about 40% and cut by food. Plasma half life 1.5 hours; intracellular half life over 25 hours. Half is excreted unchanged in urine.

HIV-1 infection (adults). - 60 kg or more: 400 mg enteric-coated capsule orally once daily. - Under 60 kg: 250 mg once daily. - With tenofovir disoproxil fumarate: 250 mg (60 kg or more) or 200 mg (under 60 kg) once daily.

Children. 120 mg/m² twice daily (infants 2 weeks to 8 months 100 mg/m² twice daily).

Dose adjustment for kidney function (adults, 60 kg or more). CrCl 30 to 59 mL/min 200 mg once daily; 10 to 29: 125 mg once daily; under 10: 125 mg once daily after dialysis on dialysis days.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 400 mg daily.

Main alternatives. Any current nucleoside backbone (tenofovir, abacavir, lamivudine, emtricitabine).

Contraindications. Hypersensitivity; co-administration with stavudine; history of pancreatitis; pregnancy combined with stavudine; heavy alcohol use.

Serious adverse effects. Pancreatitis, peripheral neuropathy, lactic acidosis with hepatic steatosis, non-cirrhotic portal hypertension, retinal depigmentation, and optic neuritis.

Common adverse effects. Diarrhoea, nausea, abdominal pain and headache.

Interactions. - Stavudine: additive toxicity; avoid. - Tenofovir disoproxil fumarate raises levels, so the dose is cut. - Ribavirin raises levels and causes fatal toxicity. - Allopurinol raises levels; avoid. - Ganciclovir raises levels; atazanavir and some antifungals absorbed with gastric acid need separation from buffered forms.

Common prescribing errors. Taking with food, combining with stavudine, and omitting the dose reduction with tenofovir.

Special groups. - Pregnancy: avoid, particularly with stavudine. - Breastfeeding: avoid. - Children: higher doses by body surface area; monitor pancreatic enzymes. - Older adults: adjust for kidney function. - Kidney impairment: reduce the dose at CrCl under 60 mL/min. - Liver impairment: caution; avoid in cirrhosis if possible.

Regional points. It has been withdrawn from first-line programmes in East Africa, so any remaining patient needs review and a switch to a current regimen.

Formulations. Enteric-coated capsules 125 mg, 200 mg, 250 mg and 400 mg (availability is limited); powder for oral solution.

Administration. On an empty stomach: at least 30 minutes before or 2 hours after a meal. Swallow capsules whole.

Baseline. Amylase, liver tests, triglycerides, neuropathy examination, creatinine, pregnancy test.

Monitoring. Symptoms of pancreatitis or neuropathy at each visit; amylase if abdominal pain; lactate if unwell.

Stopping thresholds. Stop for pancreatitis, symptomatic neuropathy, lactic acidosis or portal hypertension.

Referral and escalation. Specialist review for all patients still on didanosine, and for pancreatitis or lactic acidosis.