Coverage of 2006 International
Conference on AIDS

August 14–18, 2006, Toronto, Canada

 

More Good News of the First Integrase Inhibitor

Martin Delaney, Founding Director, Project Inform
August 16, 2006

Many of the most anticipated presentations at the conference are scheduled to take place on the last day in the form of “Late-Breaker” sessions. Much of the other material presented at the conference has been seen before at previous conferences, while the late-breakers at least offer the hope of something really new.

Of these, perhaps the one most eagerly anticipated is the first report of use of Merck’s new integrase inhibitor, MK-0518, in people who are just beginning treatment for the first time (known as treatment naïve). At earlier conferences, the company had reported on studies using the new drug in people with advanced disease and high levels of drug resistance. In that study, the drug proved to be remarkably effective, so the interest is high in seeing how it works at other stages of HIV infection.

The study reported on was designed to compare a three-drug regimen using Sustiva (efavirenz) to an otherwise identical three-drug regimen using the Merck integrase inhibitor. The two groups were well matched and study volunteers took either efavirenz or MK-0518 plus tenofovir and 3TC. The people taking MK-0518 were divided into subgroups using four different dose levels of the drug, ranging from 100mg twice daily to 400mg twice daily.

After 24 weeks, the two groups had a similar percentage of people achieving “undetectable” viral load with below 50 copies of virus detected. Approximately 80% reached this level of suppression whether treated with regimens containing efavirenz or MK-0518.

There was, however, a substantial difference in the number of CD4+ cells gained between the two groups. The group taking efavirenz had the lowest gain, roughly 110 new cells. Those taking MK-0518 generally had higher gains, with the group on the highest dose, 400mg twice daily, gaining about 175 CD4+ cells.

Despite the similar level of viral suppression achieved by the 24th week in both groups, there were indications that efavirenz and MK-0518 were performing somewhat differently. There was a large difference in how rapidly the two drugs were able to achieve viral suppression. For example, at week 4 only about 20% of volunteers on efavirenz had reached undetectable viral levels below 50 copies of virus. In contrast, at the same time point, 60–78% (depending on dose level) of those on MK-0518 had reached the same level of viral suppression. Similarly, at week 8, 37% on efavirenz were undetectable below 50 copies, compared to 75–83% of those on MK-0518.

Table 1
Regimen	% below 50 copies at week 4	% below 50 copies at week 8
Efavirenz	~20%	~37%
Mk-0518	60–78%*	75–83%*
* depending on dose level

Just what this difference in early response means is unclear, though no one doubts that it is a good sign of a drug’s potency. Some studies have suggested that drugs which produce a faster initial suppression of virus consequently are more durable and suppress virus for a longer time without developing resistance. Further studies are needed to prove this.

This study also showed no evidence of any other toxicity compared to efavirenz and some early indications of reduced toxicity. Further studies in larger numbers of people will be needed fully characterize the toxicity of this drug.

Collectively, these observations add to the growing belief that this new integrase inhibitor is very likely to be among the most potent drugs ever against HIV. It is unaffected by prior resistance to other drugs and so far seems to add little or no new toxicity. Between this and a few other new drugs, such as the protease inhibitor Prezista and the upcoming entry inhibitor maraviroc, it is likely that we are entering a new era in treating HIV, one that may change all past approaches to the treatment of the disease. Discussion is already underway about the testing of two-drug combinations, made possible by more potent new drugs, and even the use of single-drug therapy. It will take a few years to determine the best approaches, but it is all but certain that things are about to change. The change may ultimately be as significant as those which took place ten years ago when the first protease inhibitors became available. This is bound to be good news for people with HIV.