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Integrase Inhibitor Adds More Punch to Salvage Regimens
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Mark Mascolini
February 27, 2007
14th Conference on Retroviruses and Opportunistic Infections
Los Angeles
Merck's integrase inhibitor raltegravir (MK-0518) did not disappoint in early results from two international placebo-controlled trials involving people with heavy treatment experience [1,2]. When combined with the protease inhibitor darunavir or the entry inhibitor enfuvirtide in salvage regimens, raltegravir pushed viral loads below 400 copies in 90% of study participants in only 16 weeks. Almost everyone who combined all three of these drugs reached a sub-400 viral load.
David Cooper (University of New South Wales) and Roy Steigbigel (State University of New York at Stony Brook) took turns unveiling the much-anticipated results from BENCHMRK-1 (in Europe, the Asia/Pacific region, and Peru) and BENCHMRK-2 (in North and South America). The identical ongoing phase 3 studies pitted 400 mg of raltegravir twice daily against placebo, both with medleys of other antiretrovirals picked on the basis of resistance testing and treatment history. All enrollees had genotypic or phenotypic resistance to one or more drugs in each of the first three antiretroviral classes and a viral load above 1000 copies.
BENCHMRK-1 randomized 232 people to raltegravir plus an optimized background regimen (OBT) and 118 to placebo plus an OBT. Respective numbers in BENCHMRK-2 were 230 and 119. OBTs generally included three drugs. CD4 counts averaged about 150 at study entry, and starting viral loads averaged about 40,000 copies. Study participants had taken antiretrovirals for a median of 10 years. About 20% of enrollees in both trials had not tried enfuvirtide, while one quarter had not used darunavir in BENCHMRK-1 compared with about half in BENCHMRK-2.
Through 16 weeks of follow-up, a noncompleter-equals-failure analysis figured that 79% in both raltegravir arms had a viral load under 400 copies, compared with 41% and 43% in the two trials' placebo arms. Slightly more than 60% taking raltegravir reached a viral load under 50 copies in 16 weeks, compared with one third of those taking placebo. CD4 climbs averaged about 100 cells in people taking the integrase inhibitor and about 50 cells in those randomized to placebo.
Cooper counted 76 virologic failures (16%) with raltegravir plus an OBT versus 121 (51%) with placebo plus an OBT. Integrase mutations at one of two sites--N155H or Q148/R/H--usually emerged during failure. Different additional mutations arose with each of these two key mutations.
An analysis combining results of both trials determined that 98% taking both darunavir and enfuvirtide with raltegravir reached a 16-week viral load under 400 copies, compared with 87% in the placebo arm who took darunavir and enfuvirtide. While 90% taking either darunavir or enfuvirtide with raltegravir reached a sub-400 viral load, 63% taking placebo with enfuvirtide (but not darunavir) in the OBT and 55% taking placebo with darunavir (but not enfuvirtide) in the OBT got their viral load under 400 copies. Whereas 74% of people who took raltegravir with neither darunavir nor enfuvirtide got to a viral load under 400, only 29% taking placebo and neither darunavir nor enfuvirtide saw their load sink below 400. Lower baseline viral load and higher baseline CD4 count favored better responses to raltegravir (Table).
Similar proportions of enrollees, about 80% in each raltegravir or placebo arm, had at least one adverse event. About 50% in each arm had a drug-related toxicity. Only about 2% had a serious drug-related toxicity, and fewer than 2% taking raltegravir had to quit the study because of a drug side effect.
Preliminary data after 24 weeks of treatment show similar results.
Reference
1. Cooper D, Gatell J, Rockstrok J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 105aLB.
2. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study
evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 105bLB.
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