Integrase Inhibitors Show Promise in HIV Therapy : At 16 weeks, 50% of the treated patients had a viral load below 50 copies/mL.

SAN FRANCISCO — The expected introduction of the integrase inhibitors will usher in the most exciting time in HIV treatment since the advent of highly active antiretroviral therapy, Dr. George Beatty predicted at a meeting on HIV management sponsored by the University of California, San Francisco.

The drug that is furthest along in trials, MK-0518, is “one of the most potent things I have ever seen,” said Dr. Beatty, commenting on recent trial results. “Clearly, MK-0518 can really kick butt.”

In the initial study in patients, MK-0518 (Merck) reduced viral loads by 2 log10 in just 10 days, a finding that was consistent with recent, double-blind trials, said Dr. Beatty, director of the HIV clinical trials group at the University of California, San Francisco, who did not participate in the trials and who said he had no conflicts of interest regarding the manufacturer.

All of the studies were presented at HIV meetings in 2006.

In the most recent of those studies, treatment-experienced patients with serious drug-resistant disease were randomly assigned to receive one of three doses of the new drug or placebo in addition to continuing their optimized background therapy. There were about 40 patients in each group.

At 16 weeks, 50% of the patients who were treated with MK-0518 had a viral load below 50 copies/mL, regardless of which dose they received, compared with only about 20% of patients on placebo.

At 24 weeks, 67% of the patients who were on active therapy had a viral load below 50 copies/mL.

The response rate was even more impressive in the subgroup whose background medications included enfuvirtide, also known as T20, an anti-HIV entry inhibitor. Overall, 90% of those patients achieved a viral load below 50 copies/mL at 24 weeks.

The patients in this trial were difficult to treat, with resistance to at least one drug in each of the three main classes of HIV medication, Dr. Beatty noted.

“It's sexy data,” he said, of all the trials of MK-0518 to date.

Integrase inhibitors prevent DNA created by the retrovirus from becoming incorporated into the host cell DNA, thereby blocking reproduction.

MK-0518 is currently available through an expanded access research program to patients whose infection was previously uncontrolled.

A second integrase inhibitor that is “close on the heels” of MK-0518 in development is GS-9137 (Gilead), Dr. Beatty said. This drug also has shown the ability to reduce viral load by 2 log10 in about 10 days.

“It appears that Merck has not cornered the market on potency, and that this degree of potency is a class effect,” he said.

One difference between the two drugs is that MK-0518 requires twice daily dosing, while GS-9137 uses once daily dosing.

Also, MK-0518 is metabolized by glucuronidation, so it does not appear to have any significant drug-drug interactions.

GS-9137, on the other hand, is metabolized by cytochrome P3A, so it may interact with other drugs.

Also, GS-9137 can be boosted with ritonavir, while MK-0518 cannot.

So far, the drugs appear to be very well tolerated. However, one patient in the MK-0518 trial developed abnormal liver enzymes that appeared to be drug related.

In vitro data suggest that when resistance does develop, it is broad resistance to all drugs in the class, Dr. Beatty added.

SAN FRANCISCO — The expected introduction of the integrase inhibitors will usher in the most exciting time in HIV treatment since the advent of highly active antiretroviral therapy, Dr. George Beatty predicted at a meeting on HIV management sponsored by the University of California, San Francisco.

The drug that is furthest along in trials, MK-0518, is “one of the most potent things I have ever seen,” said Dr. Beatty, commenting on recent trial results. “Clearly, MK-0518 can really kick butt.”

In the initial study in patients, MK-0518 (Merck) reduced viral loads by 2 log10 in just 10 days, a finding that was consistent with recent, double-blind trials, said Dr. Beatty, director of the HIV clinical trials group at the University of California, San Francisco, who did not participate in the trials and who said he had no conflicts of interest regarding the manufacturer.

All of the studies were presented at HIV meetings in 2006.

In the most recent of those studies, treatment-experienced patients with serious drug-resistant disease were randomly assigned to receive one of three doses of the new drug or placebo in addition to continuing their optimized background therapy. There were about 40 patients in each group.

At 16 weeks, 50% of the patients who were treated with MK-0518 had a viral load below 50 copies/mL, regardless of which dose they received, compared with only about 20% of patients on placebo.

At 24 weeks, 67% of the patients who were on active therapy had a viral load below 50 copies/mL.

The response rate was even more impressive in the subgroup whose background medications included enfuvirtide, also known as T20, an anti-HIV entry inhibitor. Overall, 90% of those patients achieved a viral load below 50 copies/mL at 24 weeks.

The patients in this trial were difficult to treat, with resistance to at least one drug in each of the three main classes of HIV medication, Dr. Beatty noted.

“It's sexy data,” he said, of all the trials of MK-0518 to date.

Integrase inhibitors prevent DNA created by the retrovirus from becoming incorporated into the host cell DNA, thereby blocking reproduction.

MK-0518 is currently available through an expanded access research program to patients whose infection was previously uncontrolled.

A second integrase inhibitor that is “close on the heels” of MK-0518 in development is GS-9137 (Gilead), Dr. Beatty said. This drug also has shown the ability to reduce viral load by 2 log10 in about 10 days.

“It appears that Merck has not cornered the market on potency, and that this degree of potency is a class effect,” he said.

One difference between the two drugs is that MK-0518 requires twice daily dosing, while GS-9137 uses once daily dosing.

Also, MK-0518 is metabolized by glucuronidation, so it does not appear to have any significant drug-drug interactions.

GS-9137, on the other hand, is metabolized by cytochrome P3A, so it may interact with other drugs.

Also, GS-9137 can be boosted with ritonavir, while MK-0518 cannot.

So far, the drugs appear to be very well tolerated. However, one patient in the MK-0518 trial developed abnormal liver enzymes that appeared to be drug related.

In vitro data suggest that when resistance does develop, it is broad resistance to all drugs in the class, Dr. Beatty added.

SAN FRANCISCO — The expected introduction of the integrase inhibitors will usher in the most exciting time in HIV treatment since the advent of highly active antiretroviral therapy, Dr. George Beatty predicted at a meeting on HIV management sponsored by the University of California, San Francisco.

The drug that is furthest along in trials, MK-0518, is “one of the most potent things I have ever seen,” said Dr. Beatty, commenting on recent trial results. “Clearly, MK-0518 can really kick butt.”

In the initial study in patients, MK-0518 (Merck) reduced viral loads by 2 log10 in just 10 days, a finding that was consistent with recent, double-blind trials, said Dr. Beatty, director of the HIV clinical trials group at the University of California, San Francisco, who did not participate in the trials and who said he had no conflicts of interest regarding the manufacturer.

All of the studies were presented at HIV meetings in 2006.

In the most recent of those studies, treatment-experienced patients with serious drug-resistant disease were randomly assigned to receive one of three doses of the new drug or placebo in addition to continuing their optimized background therapy. There were about 40 patients in each group.

At 16 weeks, 50% of the patients who were treated with MK-0518 had a viral load below 50 copies/mL, regardless of which dose they received, compared with only about 20% of patients on placebo.

At 24 weeks, 67% of the patients who were on active therapy had a viral load below 50 copies/mL.

The response rate was even more impressive in the subgroup whose background medications included enfuvirtide, also known as T20, an anti-HIV entry inhibitor. Overall, 90% of those patients achieved a viral load below 50 copies/mL at 24 weeks.

The patients in this trial were difficult to treat, with resistance to at least one drug in each of the three main classes of HIV medication, Dr. Beatty noted.

“It's sexy data,” he said, of all the trials of MK-0518 to date.

Integrase inhibitors prevent DNA created by the retrovirus from becoming incorporated into the host cell DNA, thereby blocking reproduction.

MK-0518 is currently available through an expanded access research program to patients whose infection was previously uncontrolled.

A second integrase inhibitor that is “close on the heels” of MK-0518 in development is GS-9137 (Gilead), Dr. Beatty said. This drug also has shown the ability to reduce viral load by 2 log10 in about 10 days.

“It appears that Merck has not cornered the market on potency, and that this degree of potency is a class effect,” he said.

One difference between the two drugs is that MK-0518 requires twice daily dosing, while GS-9137 uses once daily dosing.

Also, MK-0518 is metabolized by glucuronidation, so it does not appear to have any significant drug-drug interactions.

GS-9137, on the other hand, is metabolized by cytochrome P3A, so it may interact with other drugs.

Also, GS-9137 can be boosted with ritonavir, while MK-0518 cannot.

So far, the drugs appear to be very well tolerated. However, one patient in the MK-0518 trial developed abnormal liver enzymes that appeared to be drug related.

In vitro data suggest that when resistance does develop, it is broad resistance to all drugs in the class, Dr. Beatty added.