MK-0518: three-quarters of highly treated patients have undetectable viral load at 24 weeks

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The experimental integrase inhibitor MK-0518 continues to show potent activity and good safety in heavily treatment-experienced patients with few remaining options for therapy, according to a late-breaking presentation on Friday at the Forty-Sixth Interscience Conference on Antiretroviral Agents and Chemotherapy in San Francisco. Just under three quarters of the highly treatment-experienced patients who received the drug achieved a viral load below 400 copies/ml within 24 weeks of starting a new regimen that contained the drug, and even in patients who had no active drugs in the background regimen, over half achieved a viral load below 400 copies/ml.

Integrase inhibitors work differently than existing classes of anti-HIV medications by preventing the virus from inserting its genetic material into human cells. Results presented previously at the International AIDS Conference in Toronto last month showed that MK-0518 demonstrated good antiviral potency in patients starting treatment for the first time.

In the present report, Beatrice Grinsztejn from Rio de Janeiro described data from a planned 24-week interim analysis of a multicentre, double-blind, dose-ranging study in treatment-experienced patients (Protocol 005). Preliminary 16-week results from this study were presented at the Thirteenth Conference on Retroviruses and Opportunistic Infections in February.



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

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.


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 drug that acts against a virus or viruses.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.


A total of 178 participants were randomly assigned to receive one of three doses of oral MK-0518 (200mg, 400mg, or 600mg twice daily), or else placebo, and started treatment. All patients also received optimised background therapy (OBT) regimens, and about one-quarter included enfuvirtide (T-20; Fuzeon).

Because some previous data suggested that MK-0518 might interact with atazanavir (Reyataz), the researchers compared patients who were and were not using atazanavir as part of their background regimens. They found no significant differences, and results from both sets of patients were combined in the present analysis.

Baseline characteristics were similar across all study arms. Most participants (about 90%) were men, with an average age of 43 years. At the time of enrolment, patients had HIV viral loads of 5000 copies/mL or higher, with a median of 4.7 log10 copies/mL; the median CD4 cell count was about 250 cells/mm3. Patients had taken antiretroviral therapy for a median duration of about nine years, and all had documented resistance to the three major approved classes of anti-HIV drugs. About half had no active agents in their background regimens as determined by the Phenosense assay.

MK-0518 at all studied doses had potent antiviral activity starting as early as Week 2, with a mean HIV RNA decrease of about 2 log10 copies/mL. After 24 weeks, in an intent-to-treat analysis that counted drop-outs as failures, 77%-80% of patients in the three MK-0518 arms experienced at least a 1 log10 decline in viral load, compared with just 18% in the placebo arm. About three-quarters of participants (70%-73%) in the MK-0518 arms had HIV RNA below 400 copies/ml, and 57%-67% had viral loads below 50 copies/ml. In the placebo arm, the corresponding rates were 16% and 14%, respectively. Virological response rates in the three MK-0518 dose arms were similar, and the differences between these arms and the placebo group were highly statistically significant

Looking at the patients who had no active drugs in their background regimens, 54-69% of those receiving MK-0518 achieved viral suppression below 400 copies/ml, compared with none in the placebo arm. For those who still had some active background drugs, the corresponding rates were 75%-84% in the MK-0518 arms and 19% in the placebo group. Use of enfuvirtide improved treatment efficacy in all arms, with about 90% of those taking MK-0518 achieving viral loads below 400 copies/ml.

Overall, MK-0518 was well-tolerated at all studied doses. Most side effects were mild to moderate, and rates were similar in the MK-0518 and placebo arms. Drop-out rates were around 20% in the MK0518 arms, compared with 69% in the placebo arm. There were more early study discontinuations due to virological failure in the placebo group, and severe side effects and drops-outs due to adverse events were uncommon in all arms (a total of four).

The researchers concluded that in patients with advanced HIV infection, failing antiretroviral therapy, and limited treatment options, MK-0518 “was generally well-tolerated” and “had potent antiretroviral activity with or without enfuvirtide.”

While other companies also have integrase inhibitors in development, MK-0518 is furthest along in the pipeline. Based on the results of this study and the study of treatment-naive patients presented in Toronto, Merck is moving forward with larger randomised trials. While all three doses worked equally well in the present study, prior research suggested that the 400mg dose offers the best trade-off of potency and safety, and this dose was selected for future trials.


Grinsztejn B 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, San Francisco, abstract H-1670b, 2006.