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Integrase Inhibitor Has Little 24-Week Impact on Lipids
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46th ICAAC, September 27-30, 2006, San Francisco
Mark Mascolini
September 27, 2006
MK-0518, the Merck integrase inhibitor, did not boost lipids when given for 24 weeks with tenofovir and 3TC in a phase 2 trial [1]. Among previously untreated people taking the highest dose of MK-0518, triglycerides dropped 28% in 24 weeks. Lipid values at 24 weeks among people randomized to MK-0518 generally differed significantly from those of people randomized to efavirenz plus the same two nucleosides.
Separate studies of MK-0518 in healthy volunteers found little evidence that MK-0518 will affect concentrations of tenofovir, ritonavir, tipranavir/ritonavir, or efavirenz in clinically meaningful ways.
The phase 2 trial analysis involved 184 people who enrolled with no antiretroviral experience, with more than 100 CD4 cells, and with a viral load of 5000 copies or more. Ages averaged in the mid-30s. Researchers assigned study participants to one of four MK-0518 doses (Table) plus 3TC and tenofovir or to efavirenz plus 3TC and tenofovir. Pretreatment lipid values were equivalent across the five study arms and in the normal range.
After 24 weeks of treatment average total cholesterol and triglyceride values usually fell slightly in all MK-0518 groups while rising in the efavirenz group (Table). People taking the highest MK-0518 dose, 600 mg twice daily, averaged a 43-mg/dL drop in triglycerides after 24 weeks of treatment, compared with a 47-mg/dL rise in the efavirenz arm.
The larger part of the cholesterol gain in efavirenz takers involved "good" high-density lipoprotein (HDL) cholesterol. The efavirenz group gained an average of about 4 mg/dL of HDL cholesterol in 24 weeks, while most of the MK-0518 groups gained about 2 mg/dL; these differences were not statistically significant.
On the other hand "bad" low-density lipoprotein (LDL) cholesterol fell slightly in all four MK-0518 arms while climbing marginally in the efavirenz group. All the LDL differences between the MK-0518 arms and the efavirenz arm were statistically significant (P < 0.05). But they are probably not clinically meaningful at this point of the study because the efavirenz group gained an average of only about 5 mg/dL from a starting level of 108 mg/dL.
An earlier report on people in this trial registered sub-50-copy response rates of 85% to 95% in the MK-0518 arms after 24 weeks [2]. This integrase inhibitor also looks exceptionally potent against virus resistant to the first three antiretroviral classes, at least in the short term [3]. Results slated for presentation later at this ICAAC meeting will update results in these treatment-experienced people.
Other studies presented on the first day of ICAAC involved MK-0518 interactions--or lack of interactions--with other antiretrovirals. Multiple doses of tipranavir/ritonavir slightly lowered the 12-hour concentration of MK-0518 given to healthy volunteers at 400 mg twice daily but did not greatly affect the area under the concentration-time curve (AUC) or maximum concentration of MK-0518 [4]. A separate study of the same dose of MK-0518 turned up no significant interactions with tenofovir [5]. A third study in healthy volunteers found that 400 mg of MK-0518 does modestly reduce the AUC, 12-hour concentration, and maximum concentration of efavirenz [6]. But lack of any effect on the time to maximum concentration of efavirenz or efavirenz half-life led these investigators to maintain that MK-0518 will not have a "clinically meaningful" interaction with efavirenz. In this study MK-0518 did not affect levels of ritonavir given at 100 mg.
Reference
1. Teppler H, Azrolan N, Chen J, et al. Differential effect of MK-0518 and efavirenz on serum lipids an lipoproteins in antiretroviral therapy (ART)-naive patients. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract H-256a.
2. Markowitz M, Nguyen BY, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0214.
3. Grinsztejn B, Nguyen BY, Katlama C, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver. Abstract 159LB.
4. Wenning LA, Hanley H, Stone J, et al. Effect of tipranavir + ritonavir on pharmacokinetics of MK-0518. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract A-374.
5. Wenning LA, Friedman E, Kost JT, et al. Lack of a significant drug interaction between MK-0518 and tenofovir disoproxil fumarate. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract A-375.
6. Iwamoto M, Wenning LA, Petry AS, et al. Minimal effect of ritonavir and efavirenz on pharmacokinetics of MK-0518. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract A-373.
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