CROI: Merck integrase inhibitor strong in highly treatment-experienced patients

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A new integrase inhibitor, MK-0518, has shown itself potent and well-tolerated in highly treatment-experienced patients. Beatriz Grinsztejn presented interim data on the activity of Merck’s novel HIV integrase inhibitor, MK-0518, in patients with multidrug-resistant virus at the Thirteenth Conference on Retroviruses and Opportunistic Infections, held this week in Denver.

MK-0518, being developed by Merck & Co, has shot to centre stage in discussions of future HIV treatment in just a few months. Phase IIa data from treatment-naïve patients were presented at the European AIDS Clinical Society conference in Dublin last November, showing a strong performance.

The data presented on Wednesday at CROI have caused considerably greater excitement however, because they show that in highly treatment-experienced patients MK-0518 exerts enough antiretroviral effect to put up to 72% of patients' viral load below 50 copies/ml within 16 weeks – despite the severe difficulty many patients faced in assembling a background regimen of active drugs. These results are unprecedented in a salvage therapy context, and if sustained in phase III studies, could offer the hope of maintaining highly treatment-experienced patients at undetectable levels of virus.



A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.


A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

MK-0518 is also attractive because it appears to have no drug interactions with other antiretrovirals. It is neither an inhibitor nor an inducer of the CYP3A enzyme, so it will not raise or lower levels of protease inhibitors or non-nucleoside reverse transcriptase inhibitors, and no dose adjustment will be needed when used with other antiretrovirals.

Study design

This multicentre study enrolled 167 HIV-positive participants with viral loads above 5,000 copies/ml and documented genotypic or phenotypic resistance to all three classes of oral antiretroviral agents (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs], and protease inhibitors PIs]).

Participants were randomly assigned to receive one of three doses of MK-0518 (200, 400, or 600mg orally twice daily) or placebo. In addition, all received optimised background therapy (OBT). Patients were stratified into two substudies based on concurrent use of atazanavir (Reyataz), which may have a hypotherical effect on MK-0518 plasma concentrations.

Baseline median CD4 cell counts ranged from 200 to 246 cells/mm3 across the three groups. Baseline phenotypic resistance testing showed that about 50% of patients had no active drugs remaining in their background regimen, 98% were resistant to all protease inhibitors.

Sixteen weeks after starting MK-0518, at least 70% of patients achieved viral loads below 400 copies/ml in all MK-0518 dose arms in both substudies. Looking at the two substudies combined, the percentages achieving viral loads below 400 copies/ml were 88% (95% confidence interval [CI] 68-97) in the 200mg arm, 85% (95% CI 65-96) in the 400mg arm, and 92% (95% CI 73-99) in the 600mg arm, compared with just 24% (95% CI 9-45) among those receiving placebo. In both substudies combined, 56-72% of patients receiving MK-0518 achieved viral loads below 50 copies/ml, compared with 8% in the placebo arm.

All patients in the MK-0518 arms achieved viral load reductions of at least –2log at week 2, although it is notable that despite the high levels of phenotypic resistant observed to background regimen drugs, the optimised background arm achieved a –0.8log reduction at this time point, suggesting some residual activity of background regimen components.

The most commonly observed drug-related adverse events (occurring in 5% or more patients in any treatment group) were diarrhoea, nausea, vomiting, fatigue, headache, flushing, injection site reactions related to T-20, and pruritus (itching). However, side-effect rates were comparable between the MK-0518 and placebo arms. The researchers reported no dose-related adverse experiences and no MK-0518 discontinuations.

Only half the patients randomised had reached the 16-week time point in this study when the 16 week analysis was conducted, so further analysis of the 24-week data will provide a great deal more information about the activity of this drug.


Grinsztejn B et al. Potent antiretroviral Effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract LB159, 2006.