The investigational integrase inhibitor raltegravir (Isentress) continues to be well tolerated and shows potent, durable virologic response out to 48 weeks in patients who are highly resistant to protease inhibitors, nucleoside analogues and non-nucleoside analogues.
These results, which largely continue the positive findings reported at earlier timepoints, were presented on Tuesday at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.
Raltegravir (MK-0518) is an investigational integrase inhibitor with no known cross-resistance with any existing antiretroviral drugs, making it a promising prospect for those with extensive resistance. Manufacturer Merck is investigating the drug’s safety and effectiveness in clinical trials.
Isentress is expected to receive formal marketing approval for use in treatment-experienced patients in the United States in October after a Food and Drug Administration advisory panel voted unanimously in favour of approval earlier this month. European regulatory review is still ongoing.
An ongoing phase IIb multi-centre, double-blind, placebo controlled study was designed to find the optimum dose of raltegravir; previous data presented as a late breaker at the 2006 ICAAC showed potent activity and a good safety profile in heavily treatment-experienced patients.
Lead investigator Beatriz Grinsztejn presented updated 48 week data in an oral session at the 47th ICAAC in Chicago. (Data from two phase III studies of raltegravir were presented at the 2007 Conference on Retroviruses and Opportunistic Infections in February and showed similar outcomes to the study presented this week.)
To be eligible for the study, patients were required to have a viral load above 5000 copies/ml and documented resistance to drugs from all the three main classes of antiretrovirals.
On entry to the study, patients had been taking anti-HIV therapy for a median of nine years, with median viral load of 4.7 log10 (just over 50,000) copies/ml. A large majority of the participants – 84% to 98% according to raltegravir dose – displayed zero phenotypic sensitivity to all licensed protease inhibitors.
Participants were randomised to receive raltegravir at 200mg twice-daily, 400mg twice-daily, 600mg twice-daily, or placebo, plus optimised background therapy (OBT) selected after resistance testing. (Significantly, tipranavir, darunavir and maraviroc were not allowed in the OBT combinations, due to lack of data on potential drug interactions with raltegravir at the time the study began.)
Due to the clear benefits of raltegravir at the 400 mg dose, participants (including those in the placebo arm) were switched to an open-label 400mg twice-daily dose of raltegravir after 24 weeks; all participants had been switched by the 48-week point. Patients with virologic failure after 16 weeks in the double-blinded study were eligible to enter an “open-label post-virologic failure” arm; official data for these patients was not presented but a response rate of roughly 50% was quoted.
Primary 48 week outcomes were the proportion of patients with a viral load below 400 copies/ml and 50 copies/ml, change in viral load from baseline, and increase in CD4 cell count.
Data on 178 patients were presented. At week 48, viral load fell by between 1.55 and 1.64 log10 in patients taking raltegravir, compared to a mean fall of only 0.28 log10 in patients originally randomised to placebo.
The following tables summarize efficacy results at 24 and at 48 weeks:
At week 24:
|Original treatment group||N||% with HIV RNA||% with HIV RNA|
|Raltegravir 200 mg||43||70 (54, 83)||65 (49, 79)|
|Raltegravir 400 mg||45||71 (56, 84)||56 (40, 70)|
|Raltegravir 600 mg||45||71 (56, 84)||67 (51, 80)|
|Placebo||45||16 (7, 30)||13 (5, 27)|
At week 48:
Original treatment group
% with HIV RNA
% with HIV RNA
Raltegravir 200 mg
69 (53, 82)
64 (48, 78)
Raltegravir 400 mg
64 (48, 78)
46 (30, 61)
Raltegravir 600 mg
71 (56, 84)
53 (38, 68)
13 (5, 27)
9 (3, 21)
Overall, those who had achieved virologic suppression on raltegravir at 24 weeks had largely maintained it to 48 weeks; 54% of patients taking any dose of raltegravir had a viral load below 50 copies/ml. There was a slight upward trend in viral load between 24 and 48 weeks, but most virologic failures were observed within the first 24 weeks.
In 34 of 35 patients experiencing virological failure with raltegravir, resistance mutations were observed at either N155 or Q148.
The safety profile at all doses of raltegravir was described as comparable to placebo, with similar rates of fatigue and gastrointestinal symptoms. Three of 133 patients (2%) experienced grade 3 ALT or AST elevations.
The investigators conclude, “in patients with limited treatment options, raltegravir at all doses had potent and durable antiretroviral effect through week 48, and was generally well tolerated.” The study is planned to continue out to 96 weeks.
Grinsztejn B et al. 48 week efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-713, 2007.