| Clinical Use|
| 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. Indinavir is rarely used in current clinical practice.
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 also have been found to be effective, although adjustment in the indinavir dosage is required. Combination with low-dose ritonavir allows less-frequent dosing of indinavir and elimination of food restrictions.(3,4)
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").
| Potential Adverse Effects|
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. Other possible side effects include nausea, diarrhea, and fatigue.
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, dyslipIdemia, 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.
| Interactions with Other Drugs|
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 dosage adjustments are frequently required, and some combinations are clearly contraindicated.
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 atazanavir, fosamprenavir, and nelfinavir (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 atazanavir, fosamprenavir, nelfinavir, and saquinavir; I84V contributes to resistance against to all available protease inhibitors.
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 may be diminished by resistance to other protease inhibitors.(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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