Efficacy of Raltegravir Sustained at Nearly 2 Years

MEXICO CITY — When raltegravir (Isentress) is used as part of combination antiretroviral therapy in treatment-naive patients infected with HIV, its efficacy is sustained and similar to that of efavirenz (Sustiva) and it appears to have a better safety profile, according to updated results of a randomized trial.

Raltegravir is an oral inhibitor of the viral integrase enzyme and has been shown to be active against a variety of HIV isolates, Dr. Martin Markowitz, lead author, said at the International AIDS Conference. The aim of the phase II trial was to compare the drug's safety and efficacy with those of efavirenz.

In the trial, patients were treated with raltegravir (100, 200, 400, or 600 mg twice daily) or efavirenz, added to the backbone of tenofovir (Viread/TDF) plus lamivudine (Epivir/3TC), reported Dr. Markowitz, a staff investigator with the Aaron Diamond AIDS Research Center in New York. The results observed with raltegravir were indistinguishable across doses at the 48-week analysis, so all of the patients were treated with the 400-mg dose thereafter.

The updated, 96-week analysis was based on data from 160 patients who were treated with raltegravir and 38 patients who were treated with efavirenz, who had a mean age of 36 years. The low dropout rate of about 15% over 96 weeks of therapy “speaks to the tolerability of both regimens,” Dr. Markowitz said.

The percentage of patients who had fewer than 400 copies/mL of viral RNA (the trial's primary end point) was identical in the raltegravir and efavirenz groups, at 84%. The percentage with fewer than 50 copies/mL was also similar, at 83% and 84%, respectively.

One patient in each trial arm experienced treatment failure in the second half of the 96-week period. Genotyping showed that the patient taking raltegravir had wild-type virus, whereas the patient taking efavirenz had resistance mutations consistent with exposure to that drug.

The rate of drug-related adverse events was 51% with raltegravir and 74% with efavirenz. The difference was driven mainly by a difference in neuropsychiatric events, Dr. Markowitz said, most of which occurred by 48 weeks. The rate for raltegravir was half of that for efavirenz at 96 weeks (16% vs. 32%).

Cancers occurred with nearly equal rates in the raltegravir and efavirenz arms (2% vs. 3%, respectively), and grade 3/4 laboratory abnormalities were uncommon for both drugs, with individual abnormalities occurring in 8% of patients at most.

However, efavirenz was associated with significantly greater unfavorable changes from baseline in levels of total cholesterol—an increase of 24%, compared with an increase of 1% with raltegravir—and low-density lipoprotein cholesterol—an increase of 4%, compared with a decrease of 6% with raltegravir.

Dr. Markowitz concluded that with the combination therapy used, raltegravir has a sustained antiretroviral efficacy similar to that at 48 weeks and to that achieved with efavirenz. In addition, it was generally well tolerated and seemed to be associated with a lower rate of adverse events.

An attendee asked if the earlier report of the more rapid virologic suppression achieved with raltegravir had any clinical importance now that the two drugs seem to have similar efficacy. Dr. Markowitz replied that differing antiviral mechanisms may explain that early finding, but the clinical importance of more rapid suppression remains uncertain.

Another attendee asked why all of the patients were put on the 400-mg dose of raltegravir if lower doses were equally efficacious, and whether a trial of once-daily dosing might not be reasonable. Dr. Markowitz replied that pharmacokinetic data show marked interpatient and intrapatient variability in drug levels, and exposure to this drug is reduced by some of the other drugs HIV-positive patients take.

The 400-mg dose was chosen in an effort to ensure that most of the patients were receiving exposures that would “appear to be consistent with a good virologic response,” he explained.

Addressing the once-daily dosing issue, he noted that the development plan for raltegravir focused on previously treated patients, but that the drug is now being used in the treatment-naive population.

“It's rare in HIV that we have actually developed drugs with different dosing plans for different patient populations. However, I think that's an interesting thought and one that certainly should be [considered] for raltegravir perhaps and other drugs, particularly as we try to roll some of these drugs out to less developed areas,” he said.

Dr. Markowitz reported that he received research grants and speaker fees from Merck Research Laboratories, which manufacturers raltegravir, and that he serves as a paid consultant for the company.

MEXICO CITY — When raltegravir (Isentress) is used as part of combination antiretroviral therapy in treatment-naive patients infected with HIV, its efficacy is sustained and similar to that of efavirenz (Sustiva) and it appears to have a better safety profile, according to updated results of a randomized trial.

Raltegravir is an oral inhibitor of the viral integrase enzyme and has been shown to be active against a variety of HIV isolates, Dr. Martin Markowitz, lead author, said at the International AIDS Conference. The aim of the phase II trial was to compare the drug's safety and efficacy with those of efavirenz.

In the trial, patients were treated with raltegravir (100, 200, 400, or 600 mg twice daily) or efavirenz, added to the backbone of tenofovir (Viread/TDF) plus lamivudine (Epivir/3TC), reported Dr. Markowitz, a staff investigator with the Aaron Diamond AIDS Research Center in New York. The results observed with raltegravir were indistinguishable across doses at the 48-week analysis, so all of the patients were treated with the 400-mg dose thereafter.

The updated, 96-week analysis was based on data from 160 patients who were treated with raltegravir and 38 patients who were treated with efavirenz, who had a mean age of 36 years. The low dropout rate of about 15% over 96 weeks of therapy “speaks to the tolerability of both regimens,” Dr. Markowitz said.

The percentage of patients who had fewer than 400 copies/mL of viral RNA (the trial's primary end point) was identical in the raltegravir and efavirenz groups, at 84%. The percentage with fewer than 50 copies/mL was also similar, at 83% and 84%, respectively.

One patient in each trial arm experienced treatment failure in the second half of the 96-week period. Genotyping showed that the patient taking raltegravir had wild-type virus, whereas the patient taking efavirenz had resistance mutations consistent with exposure to that drug.

The rate of drug-related adverse events was 51% with raltegravir and 74% with efavirenz. The difference was driven mainly by a difference in neuropsychiatric events, Dr. Markowitz said, most of which occurred by 48 weeks. The rate for raltegravir was half of that for efavirenz at 96 weeks (16% vs. 32%).

Cancers occurred with nearly equal rates in the raltegravir and efavirenz arms (2% vs. 3%, respectively), and grade 3/4 laboratory abnormalities were uncommon for both drugs, with individual abnormalities occurring in 8% of patients at most.

However, efavirenz was associated with significantly greater unfavorable changes from baseline in levels of total cholesterol—an increase of 24%, compared with an increase of 1% with raltegravir—and low-density lipoprotein cholesterol—an increase of 4%, compared with a decrease of 6% with raltegravir.

Dr. Markowitz concluded that with the combination therapy used, raltegravir has a sustained antiretroviral efficacy similar to that at 48 weeks and to that achieved with efavirenz. In addition, it was generally well tolerated and seemed to be associated with a lower rate of adverse events.

An attendee asked if the earlier report of the more rapid virologic suppression achieved with raltegravir had any clinical importance now that the two drugs seem to have similar efficacy. Dr. Markowitz replied that differing antiviral mechanisms may explain that early finding, but the clinical importance of more rapid suppression remains uncertain.

Another attendee asked why all of the patients were put on the 400-mg dose of raltegravir if lower doses were equally efficacious, and whether a trial of once-daily dosing might not be reasonable. Dr. Markowitz replied that pharmacokinetic data show marked interpatient and intrapatient variability in drug levels, and exposure to this drug is reduced by some of the other drugs HIV-positive patients take.

The 400-mg dose was chosen in an effort to ensure that most of the patients were receiving exposures that would “appear to be consistent with a good virologic response,” he explained.

Addressing the once-daily dosing issue, he noted that the development plan for raltegravir focused on previously treated patients, but that the drug is now being used in the treatment-naive population.

“It's rare in HIV that we have actually developed drugs with different dosing plans for different patient populations. However, I think that's an interesting thought and one that certainly should be [considered] for raltegravir perhaps and other drugs, particularly as we try to roll some of these drugs out to less developed areas,” he said.

Dr. Markowitz reported that he received research grants and speaker fees from Merck Research Laboratories, which manufacturers raltegravir, and that he serves as a paid consultant for the company.

MEXICO CITY — When raltegravir (Isentress) is used as part of combination antiretroviral therapy in treatment-naive patients infected with HIV, its efficacy is sustained and similar to that of efavirenz (Sustiva) and it appears to have a better safety profile, according to updated results of a randomized trial.

Raltegravir is an oral inhibitor of the viral integrase enzyme and has been shown to be active against a variety of HIV isolates, Dr. Martin Markowitz, lead author, said at the International AIDS Conference. The aim of the phase II trial was to compare the drug's safety and efficacy with those of efavirenz.

In the trial, patients were treated with raltegravir (100, 200, 400, or 600 mg twice daily) or efavirenz, added to the backbone of tenofovir (Viread/TDF) plus lamivudine (Epivir/3TC), reported Dr. Markowitz, a staff investigator with the Aaron Diamond AIDS Research Center in New York. The results observed with raltegravir were indistinguishable across doses at the 48-week analysis, so all of the patients were treated with the 400-mg dose thereafter.

The updated, 96-week analysis was based on data from 160 patients who were treated with raltegravir and 38 patients who were treated with efavirenz, who had a mean age of 36 years. The low dropout rate of about 15% over 96 weeks of therapy “speaks to the tolerability of both regimens,” Dr. Markowitz said.

The percentage of patients who had fewer than 400 copies/mL of viral RNA (the trial's primary end point) was identical in the raltegravir and efavirenz groups, at 84%. The percentage with fewer than 50 copies/mL was also similar, at 83% and 84%, respectively.

One patient in each trial arm experienced treatment failure in the second half of the 96-week period. Genotyping showed that the patient taking raltegravir had wild-type virus, whereas the patient taking efavirenz had resistance mutations consistent with exposure to that drug.

The rate of drug-related adverse events was 51% with raltegravir and 74% with efavirenz. The difference was driven mainly by a difference in neuropsychiatric events, Dr. Markowitz said, most of which occurred by 48 weeks. The rate for raltegravir was half of that for efavirenz at 96 weeks (16% vs. 32%).

Cancers occurred with nearly equal rates in the raltegravir and efavirenz arms (2% vs. 3%, respectively), and grade 3/4 laboratory abnormalities were uncommon for both drugs, with individual abnormalities occurring in 8% of patients at most.

However, efavirenz was associated with significantly greater unfavorable changes from baseline in levels of total cholesterol—an increase of 24%, compared with an increase of 1% with raltegravir—and low-density lipoprotein cholesterol—an increase of 4%, compared with a decrease of 6% with raltegravir.

Dr. Markowitz concluded that with the combination therapy used, raltegravir has a sustained antiretroviral efficacy similar to that at 48 weeks and to that achieved with efavirenz. In addition, it was generally well tolerated and seemed to be associated with a lower rate of adverse events.

An attendee asked if the earlier report of the more rapid virologic suppression achieved with raltegravir had any clinical importance now that the two drugs seem to have similar efficacy. Dr. Markowitz replied that differing antiviral mechanisms may explain that early finding, but the clinical importance of more rapid suppression remains uncertain.

Another attendee asked why all of the patients were put on the 400-mg dose of raltegravir if lower doses were equally efficacious, and whether a trial of once-daily dosing might not be reasonable. Dr. Markowitz replied that pharmacokinetic data show marked interpatient and intrapatient variability in drug levels, and exposure to this drug is reduced by some of the other drugs HIV-positive patients take.

The 400-mg dose was chosen in an effort to ensure that most of the patients were receiving exposures that would “appear to be consistent with a good virologic response,” he explained.

Addressing the once-daily dosing issue, he noted that the development plan for raltegravir focused on previously treated patients, but that the drug is now being used in the treatment-naive population.

“It's rare in HIV that we have actually developed drugs with different dosing plans for different patient populations. However, I think that's an interesting thought and one that certainly should be [considered] for raltegravir perhaps and other drugs, particularly as we try to roll some of these drugs out to less developed areas,” he said.

Dr. Markowitz reported that he received research grants and speaker fees from Merck Research Laboratories, which manufacturers raltegravir, and that he serves as a paid consultant for the company.