Prodrug of deoxyadenosine nucleoside analogue
| Clinical Use|
Many antiretroviral combinations containing didanosine have been found to be effective at suppressing HIV viral load and increasing CD4 cell counts, and in some studies, prolonging AIDS-free survival.
Didanosine should not be administered concurrently with certain medications because of additive or overlapping potential adverse effects. For example, the combination of didanosine and stavudine should be avoided because of increased toxicity (peripheral neuropathy and hyperlactatemia), and should not be used in pregnant women because of reports of lactic acidosis with pancreatitis or hepatic steatosis.
Coadministration of ribavirin with didanosine may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia, and peripheral neuropathy. Patients receiving didanosine together with other potentially neurotoxic drugs (such as isoniazid or vincristine) should be monitored closely for the development of neuropathic symptoms.
Coadministration of tenofovir with didanosine increases serum levels of didanosine; dose reduction of didanosine is recommended.(4) Didanosine tablets or powder should not be taken at the same time as indinavir or delavirdine because the buffer present in the tablets interferes with the absorption of these drugs. Didanosine enteric-coated capsules do not appear to interact with indinavir.
In a small pilot study of initial therapy, the triple-nucleoside analogue combination of didanosine + lamivudine + tenofovir, showed virologic failure in 91% of patients at week 12.(5) In 2 studies, the combination of didanosine + tenofovir + efavirenz has demonstrated high rates of early virologic failure in treatment-naive individuals with high HIV RNA and low CD4 levels at baseline.(6,7) The reasons for the failure of these combinations is not clear; pending further study, they should be avoided.
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services state that didanosine is "not recommended" for initial antiretroviral therapy, because of higher rates of toxicity than recommended nucleoside anlaogues. The combination of didanosine + stavudine is "not recommended" at any time, because of high rates of toxicity, including peripheral neuropathy, lipoatrophy, and lactic acidosis.
Didanosine may be useful in subsequent therapies (see "Resistance" below).
| Factors Affecting Adherence|
Symptomatic side effects of didanosine include diarrhea, which results from the large amount of buffer in the tablet and powder forms and is less of a problem with the enteric-coated capsules, and peripheral neuropathy, which may range in severity from mild to disabling. Heavy or episodically heavy alcohol use may increase the risk of potentially fatal pancreatitis. The "empty-stomach" requirement may affect adherence, especially when twice-daily dosing is used. The once-daily dosing afforded by the enteric-coated formulation may facilitate adherence, but this formulation must still be taken on an empty stomach.
There is evidence that nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of lipid metabolism.(8) It is important to assess patient motivation and discuss scheduling as well as possible side effects and strategies for their management before treatment with didanosine is initiated.
|| || Dolin R, Amato DA, Fischl MA, et al. Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group. Arch Intern Med. 1995 May 8;155(9):961-74.|
|| || Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med. 1996 Oct 10;335(15):1091-8.|
|| || Englund JA, Baker CJ, Raskino C, et al. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. N Engl J Med. 1997 Jun 12;336(24):1704-12.|
|| ||Kearney BP, Isaacson E, Sayre J, et al. Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 9-14, 2002; Seattle. Abstract 533. |
|| ||Jemsek J, Hutcherson P, and Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 51.|
|| || Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-7.|
|| || Maitland D, Moyle G, Hand J, et al. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS. 2005 Jul 22;19(11):1183-8. |
|| || Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.|