| Clinical Use|
Regimens consisting of 2 nucleoside analogues and indinavir have been found to provide potent suppression of viral load in previously untreated patients. Several regimens containing indinavir in combination with nonnucleoside reverse transcriptase inhibitors have also been found to be effective, although adjustment in the indinavir dose is required. Combination with low-dose ritonavir allows less-frequent dosing of indinavir and elimination of food restrictions.(3,4)
Indinavir is an inhibitor of cytochrome P450 3A4 (CYP3A4), and may alter serum concentrations of other drugs metabolized by this pathway, including certain benzodiazepines, cholesterol-lowering agents, ergot derivatives, rifampin, phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, or vardenafil), and others. Because indinavir is also metabolized by CYP3A4, drugs that affect this enzyme system, such as ketoconazole, rifampin, and rifabutin, may significantly affect indinavir levels. Several protease inhibitors and the nonnucleoside reverse transcriptase inhibitors also affect indinavir concentrations. For example, indinavir concentrations are decreased by efavirenz and nevirapine; indinavir must be boosted with low-dose ritonavir when it is used in combination with nevirapine or efavirenz.
Even though both indinavir and didanosine are taken on an empty stomach, the tablet or powder formulations of didanosine should not be taken at the same time as indinavir because the buffer in these formulations may interfere with indinavir absorption. Indinavir should not be coadministered with atazanavir because of increased risk of hyperbilirubinemia.
Information on drug interactions should be consulted, as dose adjustments are frequently required, and some combinations are clearly contraindicated.
| Use in Initial vs Subsequent Therapy|
Treatment guidelines of the U.S. Department of Health and Human Services designate indinavir and ritonavir-boosted indinavir as "not recommended" for initial treatment of HIV infection.
Failure of a regimen containing indinavir may decrease the likelihood that subsequent protease inhibitor-containing regimens will succeed. Similarly, the response to indinavir is often diminished following virologic relapse on a regimen containing another protease inhibitor (see "Resistance").
| Factors Affecting Adherence|
The most common serious symptomatic side effect of indinavir is nephrolithiasis (kidney stones). The risk of stones is reduced by maintaining adequate hydration. Intake of least 48 ounces (1.5 liter) of water per 24-hour period is recommended for individuals taking indinavir, and more may be needed in hot weather or with sweating or diarrhea.
Fluid requirements, frequent dosing, and dietary restrictions make adherence to indinavir particularly challenging. Combination with ritonavir may simplify the dosing interval and dietary restrictions, but does not eliminate the risk of nephrolithiasis.
Indinavir has been associated with metabolic abnormalities including hyperglycemia, dyslipedemia, and abnormalities in fat distribution.
It is essential to assess patient motivation and discuss possible side effects and strategies for their management before treatment with indinavir is initiated.
Resistance to indinavir is associated with the selection of 1 or more of several resistance mutations.
| Implications of indinavir resistance for treatment with other antiretrovirals|
Resistance mutations selected by indinavir frequently confer or contribute to resistance against other protease inhibitors. Different mutations are associated with cross-resistance to different drugs. For example, M46I is associated with cross-resistance to ritonavir, nelfinavir, and amprenavir (but not to saquinavir); V82A,F,T,S alone is associated with cross-resistance to ritonavir, but in combination with other mutations also confers resistance to nelfinavir, amprenavir, and saquinavir; and I84V contributes to resistance against to all available protease inhibitors. Although no single one of these mutations is associated with full resistance to lopinavir or tipranavir, each contributes partial resistance, and the presence of several mutations together can confer resistance.
Response to ritonavir is unlikely in the setting of resistance to indinavir.
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing indinavir.
| Implications of resistance to other antiretrovirals for indinavir treatment|
Response to indinavir is unlikely in the setting of resistance ritonavir.
Response to indinavir may be diminished by resistance to saquinavir.(5)
Genotypic or phenotypic resistance testing may be useful in predicting the likelihood of response to indinavir following failure of regimens containing other protease inhibitors.
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|| || Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ, Feinberg JE, Balfour HH, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997;337:725-33.|
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|| || Dragsted UB, Gerstoft J, Pedersen C, Peters B, Duran A, Obel N, Castagna A, Cahn P, Clumeck N, Bruun JN, Benetucci J, Hill A, Cassetti I, Vernazza P, Youle M, Fox Z, Lundgren JD; MaxCmin1 Trial Group. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis. 2003 Sep 1;188(5):635-42. Epub 2003 Aug 20.|
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