| Clinical Use|
Rapid emergence of viral breakthrough occurs when amprenavir is used as monotherapy.(3) As with other antiretrovirals, amprenavir should be used only in combination regimens.
Amprenavir is metabolized by the cytochrome P450 3A4 (CYP3A4) isoenzyme, and may alter the concentrations of other drugs metabolized by this pathway, including rifabutin, antiarrhythmics, tricyclic antidepressants, certain benzodiazepines, ergot derivatives, and others. Similarly, drugs that induce or inhibit the action of this isoenzyme may cause therapeutically significant alterations in amprenavir levels. For example, rifampin induces CYP3A4, and markedly decreases amprenavir levels. Information on drug interactions should be consulted, as dose adjustments are frequently required and some combinations are contraindicated.
Although amprenavir has been studied in combination with all previously available protease inhibitors, in most cases precise information on dosing in combination with other antiretrovirals is lacking. Coadministration with lopinavir/ritonavir (Kaletra) may decrease amprenavir levels, and may require dose-adjustment of amprenavir.(4,5) Coadministration with efavirenz has been shown to decrease amprenavir levels, but increasing the amprenavir dose or adding ritonavir may boost amprenavir to therapeutic levels in combination with efavirenz.(6)
| Use in Initial vs Subsequent Therapy|
Treatment guidelines of the U.S. Department of Health and Human Services do not recommend amprenavir-containing regimens for initial treatment of HIV infection. The guidelines do include the amprenavir prodrug, fosamprenavir.
Because amprenavir became available some time after the initial group of protease inhibitors, and because its associated resistance mutations differ from those of the other protease inhibitors, it has been studied as a possible component of salvage therapy in multiple-drug-experienced individuals. Efficacy in this situation appears to be modest. In protease inhibitor-experienced individuals, amprenavir plus a second protease inhibitor appears to be more effective than amprenavir alone in combination with NRTIs and efavirenz.(7)
| Factors Affecting Adherence|
Symptomatic side effects of amprenavir include rash, headache, diarrhea, and nausea. The amprenavir prodrug, fosamprenavir, has fewer gastrointestinal side effects. Amprenavir oral solution contains propylene glycol and should be avoided in certain patients, including pregnant women, young children, and those with renal or hepatic failure. It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with amprenavir is initiated.
Resistance to amprenavir is associated with the selection of 1 or more of several resistance mutations.
| Implications of amprenavir resistance for treatment with other antiretrovirals|
One resistance mutation (I50V) commonly selected by amprenavir does not appear to confer cross-resistance to other protease inhibitors, whereas others (I84V, M46I) confer or contribute to resistance against other protease inhibitors. In one study,(8) participants previously treated with amprenavir monotherapy showed long-term suppression of viral load after switching to a regimen of nevirapine + indinavir + stavudine + lamivudine. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing amprenavir.
| Implications of resistance to other antiretrovirals for amprenavir treatment|
A minority of individuals with HIV resistant to other protease inhibitors may respond to regimens including amprenavir. The addition of a second protease inhibitor appears to improve the rate of virologic response in highly drug-experienced patients.(7)
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to amprenavir following failure of regimens containing other antiretrovirals.
|| || Notermans DW, Jurriaans S, de Wolf F, Foudraine NA, de Jong JJ, Cavert W, Schuwirth CM, Kauffmann RH, Meenhorst PL, McDade H, Goodwin C, Leonard JM, Goudsmit J, Danner SA. Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. Ritonavir/3TC/ZDV Study Group. AIDS 1998;12:167-73.|
|| ||Discontinuation of Agenerase (amprenavir) Oral Solution and 50 mg Capsules in the US. Dear Healthcare Professional. GlaxoSmithKline: Research Triangle Park, North Carolina, August 2007. Available online at http://www.fda.gov/CDER/Drug/shortages/AGN-DC%20DHP%20Letter.pdf.|
|| || Goodgame JC, Pottage JC, Jablonowski H, Hardy WD, Stein A, Fischl M, Morrow P, Feinberg J, Brothers CH, Vafidis I, Nacci P, Yeo J, Pedneault L. Amprenavir in combination with lamivudine and zidovudine versus lamivudine and zidovudine alone in HIV-1-infected antiretroviral-naive adults. Amprenavir PROAB3001 International Study Team. Antivir Ther 2000;5:215-25.|
|| || Taburet AM, Raguin G, Le Tiec C, Droz C, Barrail A, Vincent I, Morand-Joubert L, Chene G, Clavel F, Girard PM. Interactions between amprenavir and the lopinavir-ritonavir combination in heavily pretreated patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 2004 Apr;75(4):310-23. |
|| || Basso S, Solas C, Quinson AM, Ravaux I, Poizot-Martin I, Bacconier J, Durand A, Lacarelle B. Pharmacokinetic interaction between lopinavir/r and amprenavir in salvage therapy. J Acquir Immune Defic Syndr. 2002 Sep 1;31(1):115-7.|
|| ||Piscitelli S, Bechtel C, Sadler B, Falloon J. The Addition of a Second Protease Inhibitor Eliminates Amprenavir-Efavirenz Drug Interactions and Increases Plasma Amprenavir Concentrations. Abstract 78. 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco.|
|| || Hammer SM, Vaida F, Bennett KK, Holohan MK, Sheiner L, Eron JJ, Wheat LJ, Mitsuyasu RT, Gulick RM, Valentine FT, Aberg JA, Rogers MD, Karol CN, Saah AJ, Lewis RH, Bessen LJ, Brosgart C, DeGruttola V, Mellors JW; AIDS Clinical Trials Group 398 Study Team. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA. 2002 Jul 10;288(2):169-80.|
|| || Gulick RM, Smeaton LM, D'Aquila RT, Eron JJ, Currier JS, Gerber JG, Acosta E, Sommadossi JP, Tung R, Snyder S, Kuritzkes DR, Murphy RL. Indinavir, Nevirapine, Stavudine, and Lamivudine for Human Immunodeficiency Virus-Infected, Amprenavir-Experienced Subjects: AIDS Clinical Trials Group Protocol 373. J Infect Dis 2001;183:715-721.|