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Integrase Inhibitor Shows Strength in Treatment Experienced
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46th ICAAC, September 27-30, 2006, San Francisco
Mark Mascolini
September 29, 2006
MK-0518, the integrase inhibitor being developed by Merck, pushed viral loads down by an average 2 log copies/mL (100-fold) in people with heavy treatment experience, half of whom had phenotypic sensitivity scores indicating they had no effective drugs to combine with this novel drug [1]. Over 60% of people taking MK-0518 reached a viral load below 50 copies in 24 weeks, and about 90% did so if they took enfuvirtide for the first time with the integrase inhibitor.
Researchers in Brazil, France, Spain, and the US randomized study candidates to combine 200, 400, or 600 mg or MK-0518 twice daily or placebo with an optimized background regimen. Everyone had documented resistance to one or more drugs from each of the first three antiretroviral classes, a viral load above 5000 copies and a CD4 count above 50.
Viral loads at entry averaged 4.6 to 4.8 log copies/mL across the five study arms, each of which included 43 to 45 people. CD4 counts averaged 245 in the 200-mg arm, 221 in the 400-mg arm, 220 in the 600-mg arm, and 274 in the placebo arm. Median duration of antiretroviral experience was 9 or 10 years in each treatment group, and each group had taken a median of four antiretroviral regimens. Proportions of enrollees with a phenotypic sensitivity score of 0 to all antiretrovirals--meaning they had no active drugs left--were 47% in the 200-mg group, 58% in the 400-mg group, 49% in the 600-mg group, and 42% in the placebo group. Almost no one in any group had an active protease inhibitor to use. About one quarter of study participants took enfuvirtide for the first time in this trial.
Eight to 10 people (18% to 23%) in each of the MK-0518 arms quit the study before week 24, compared with 31 (69%) in the placebo group. Most people who dropped out of the study early did so because their regimen wasn't working. Three people in the MK-0518 groups and 1 in the placebo group quit because of treatment-related problems.
After 24 weeks of treatment a noncompleter-equals-failure analysis figured that 57% to 67% in the integrase inhibitor arms had a viral load under 50 copies, compared with 14% in the placebo group. About 80% taking MK-0518 had a load below 400 copies. Seven of 13 people in the 200-mg group with a baseline phenotypic sensitivity score of 0 reached a viral load below 400 copies in 24 weeks, as did 9 of 13 in the 400-mg group and 8 of 13 in the 600-mg group. No one in the placebo arm who started the study with a phenotypic sensitivity score of 0 had a week-24 viral load under 400 copies.
Using enfuvirtide for the first time boosted sub-400 copy response rates about 20% in all treatment arms, including the placebo arm. While about 60% of people in the MK-0518 groups who did not take enfuvirtide notched a sub-400 load in 24 weeks, about 90% who took the integrase inhibitor with enfuvirtide had a 24-week load under 400 copies. That finding reinforces advice to avoid using novel antiretrovirals one at a time, if at all possible, waiting instead until at least two can be combined.
Of the 178 people who signed up for this study, only 4 dropped out because of a clinical problem or dangerous lab reading. Study clinicians did report four drug-related serious side effects, including acute pancreatitis (thought to be caused by the background regimen), lacunar infarction, a type of stroke (in the placebo group), and lipoatrophy. One person died with metabolic acidosis and renal insufficiency.
Research reported at the August International AIDS Conference showed that MK-0518 quickly controls viral replication in people starting their first antiretroviral regimen [2].
References
1. Grinsztejn B, Nguyen B, Katlama C, et al. Potent efficacy of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract H-1383.
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.
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