Pharmacy & Therapeutics- August 2008 - (Page 447) DRUG FORECAST cells/mm3, compared with the placebo group, which had an average of 64 (91.41) cells/mm3. During the study, a total of 12 category C AIDS-defining illnesses or deaths occurred, as defined by the Centers for Disease Control and Prevention (CDC); eight patients (3%) had received etravirine and 21 patients (7%) received placebo.4 Table 2 Virological and Immunological Responses of Patients with HIV-1 Infection at Week 24: DUET and DUET Pooled Analysis -1 -2 Etravirine + BR (n = 599) <50 HIV-1 RNA (% copies/mL) Median CD4+ change (cells/mm3) 59.8 81 Placebo + BR (n = 604) 40.2 64 The DUET-2 Trial DUET-2 also involved treatmentexperienced patients with infection that was resistant to NNRTI therapy. This study was designed to compare the extended efficacy, safety, and tolerability of etravirine and placebo for up to 96 weeks. Data were collected in 103 centers in 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, and the U.S.). This study enrolled 593 participants who were randomly assigned to treatment; however, two patients withdrew before therapy began. Data for 591 patients were collected until January 18, 2007, after at least 24 weeks of treatment. Fifty-one etravirine patients (17%) and 73 placebo patients (25%) withdrew from the study because of virological failure. Baseline measurements revealed that 382 patients (65%) had two or more NNRTI resistance– associated mutations and 533 patients (90%) had four or more NNRTI resistance–associated mutations. The baseline evaluation for primar y PI mutations showed that 387 (66%) patients had four or more mutations and 261 (44%) had three or more darunavir resistance– associated mutations. The data that were collected during this extended trial clearly revealed that the etravirine group attained better virological responses than the placebo group. At week 24, the etravirine patients far surpassed the placebo patients in achieving a confirmed viral load of less than 50 copies/mL, less than 400 copies/ mL, and a mean change in viral load. The etravirine patients had better response rates to therapy regardless of their baseline viral load.5 BR = background regimen; HIV = human immunodeficiency virus. From etravirine (Intelence), package insert, January 2008.6 ef fects (ADEs). During the DUET-1 treatment period, 282 participants (93%) receiving etravirine and 287 participants (93%) receiving placebo reported at least one ADE. The most common ADEs occurring in 10% or more of patients in either group included rash, nausea, diarrhea, and headache. Fatigue, abdominal pain, hyper tension, pneumonia, and peripheral neuropathy were noted in 1% or more of patients in either group. The development of any type of rash was documented in 61 etravirine patients (20%) and in 30 placebo patients (10%). Rash occurred more frequently with etravirine than with placebo (16.9% vs. 9.3%, respectively), as did nausea (13.9% vs. 11.1%, respectively). Serious skin reactions such as Stevens–Johnson syndrome and erythema multiforme were reported during this study. ADEs resulted in an equal number of patients (i.e., 16 participants [5%]) from both the etravirine and placebo groups discontinuing treatment. ADE-related deaths included four etravirine patients and eight placebo patients who had started therapy during the treatment period. None of the deaths was caused as a result of any single therapeutic component of etravirine. Laboratory parameters did not reveal clinically significant differences between etravirine and placebo. When compared with placebo, etravirine did not illustrate any applicable outcome in terms of lipid concentrations, including triglycerides. Abnormal grade 3 and 4 laborator y values associated with lipid, hepatic, and pancreatic levels were equivalent in both treatment groups.4,5 ADVERSE DRUG EVENTS Although HAART remains the standard of care for HIV-1 infection, it is also associated with numerous adverse drug DRUG INTERACTIONS AND CONTRAINDICATIONS Although there were no known contraindications with etravirine at the time of the FDA’s approval,6 a number of medica- tions are not currently recommended for use with etravirine as a result of drug interactions.7 Etravirine is a substrate of the CYP 3A4, CYP 2C9, and CYP 2C19 enzymes; an inducer of CYP 3A4; and an inhibitor of CYP 2C9 and CYP 2C19. Many significant interactions may occur when additional drugs are taken in combination with other antiretroviral agents. Serum concentrations of atazanavir (Reyataz, Bristol-Myers Squibb), maraviroc (Selzentry, Pfizer), and raltegravir (Isentress, Merck) are decreased when they are taken concomitantly with etravirine. Etravirine increases the serum concentration of fosamprenavir (Lexiva, GlaxoSmithKline) when both agents are used simultaneously. Etravirine levels are considerably decreased when used with tipranavir, full-dose ritonavir (Norvir), efavirenz (Sustiva), and nevirapine (Viramune). Moderate levels of etravirine are decreased with saquinavir (Inverase, Roche), darunavir (Prezista), and tenofovir (Viread, Gilead). Etravirine concentrations are increased by lopinavir/ritonavir (Kaletra, Abbott) and delavirdine (Rescriptor). Because of the large elevation in etravirine levels with the concomitant use of Kaletra, etravirine should be prescribed with caution.6,7 Etravirine should not be administered with other NNRTIs, unboosted PIs, atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir. Close monitoring and dosage adjustments are required when interacting antiretroviral agents are included in the patient’s regimen.6 Drug interactions also exist between etravirine and other non-HAART medications. Because of the litany of drug interactions that may occur, the patient’s complete medication profile should be reviewed before etravirine treatment begins. The concentrations of some antiarrhythmic medications, such as bepridil (Vascor, Ortho-McNeil), amiodarone continued on page 491 Vol. 33 No. 8 • August 2008 • P&T® 447
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