Isentress/Truvada Comparable to Sustiva/Truvada After Three Years

Isentress (raltegravir)–based antiretroviral (ARV) therapy appears to work just as well as Sustiva (efavirenz)–inclusive regimens (such as Atripla), with fewer blood lipid problems, for at least three years in first-time HIV treatment takers, according to long-term follow-up data from Merck’s STARTMRK study published in the October 15 issue of Clinical Infectious Diseases.

The July 2009 approval of Isentress for people living with HIV starting therapy for the first time—it was initially approved for treatment-experienced patients in October 2007—was based on 48-week data from Merck’s STARTMRK study comparing Isentress and Truvada (tenofovir plus emtricitabine) with Sustiva and Truvada. After one year of treatment in STARTMRK, 87 percent of those taking Isentress had an undetectable viral load after 48 weeks of treatment compared with 82 percent of those taking Sustiva. Isentress was therefore judged to have equivalent effectiveness to Sustiva.

As is typical with Phase III studies comparing two standard-of-care regimens, the STARTMRK researchers have opted to follow patients beyond the pre-determined 48- and 96-week trial period—for up to five years—to monitor the long-term safety and efficacy of Isentress. Three-year follow-up data were published in Clinical Infectious Diseases by Jürgen Rockstroh, MD, of the University of Bonn in Bonn-Venusberg, Germany, and his STARTMRK colleagues.

STARTMRK enrolled 563 previously untreated HIV-positive individuals to receive either 400 milligrams (mg) Isentress twice daily or 600 mg Sustiva once daily, both in combination with Truvada. At study entry, the average viral load was about 100,000 copies and the average CD4 count was 218 cells.

After three years of treatment, according to the strictest data analysis performed by Rockstroh’s team, about 75 percent of Isentress-treated patients had undetectable viral loads (below 50 copies), compared with 68 percent of patients in the Sustiva group. Though Isentress appeared to do a better job of maintaining undetectable viral loads throughout the prolonged follow-up period, the study was not designed to determine the statistical superiority of one regimen over another.

Pre-treatment viral loads—either over or under 50,000 copies—didn’t affect success rates in either study group, nor did gender, age, race or pre-treatment CD4 cell counts.
Rates of virologic failure and resistance were also reported. In the Isentress group, about 17 percent experienced rebounds in viral load during the follow-up period, compared with 19 percent in the Sustiva group.

In the Isentress group, 19 patients had viral loads above 400. Their blood samples were tested for drug resistance, and of the 19, four had evidence of resistance to raltegravir. In three of these four cases, resistance to the emtricitabine in Truvada was also detected.

In the Sustiva group, seven of 19 drug resistance-tested patients had evidence of resistance to efavirenz. In three of these cases, resistance to emtricitabine was also detected.

CD4 cell counts also increased in both study groups. Among those receiving Isentress, CD4s increased 332 cells over pre-treatment levels after three years of treatment. Among those receiving Sustiva, CD4s increased by 295 cells.

Metabolic parameters—such as blood lipids and body composition changes—were also reported by Rockstroh’s group. Average levels of total cholesterol, “good” HDL cholesterol, “bad” LDL cholesterol and triglycerides were all more likely to increase in the Sustiva group compared with the Isentress group—all statistically significant differences, meaning they were unlikely due to chance.

Moderate to severe increases in total cholesterol, LDL cholesterol and triglycerides, to levels above those considered healthy, also appeared to be more common among those receiving Sustiva compared with Isentress. It was not clear, however, from the data presented that these differences were statistically significant.

A small number of patients (25 in the Isentress group and 32 in the Sustiva group) participated in studies evaluating changes in body composition, using dual energy x-ray absorptiometry (DEXA) scans conducted before starting treatment and after three years. Patients in both groups experienced increases in trunk fat, with a trend toward greater increases in the Isentress group (a 38 percent gain versus a 21 percent gain in the Sustiva group). The amount of fat in the extremities—such as the arms and legs—also increased in both groups, ranging from a 17 percent limb fat increase in the Isentress group and a 25 percent limb fat increase in the Sustiva group. Rockstroh and his colleagues noted that the rises in both trunk and limb fat were “modest” and characteristic of the “return to health” phenomenon.

As for general tolerability of the two agents, Rockstroh’s team noted that the overall incidence of drug-related side effects was lower for patients receiving Isentress compared with Sustiva (50 percent versus 80 percent), likely due to the central nervous system side effects of Sustiva.

“Our results confirm that raltegravir combined with tenofovir/emtricitabine is a durably efficacious and generally well-tolerated combination for treatment-naive patients,” the study authors concluded.

However, Rockstroh’s group acknowledged that that the regimens administered in the study were more complex than the corresponding regimens actually employed in clinical practice, which may limit their real-world applicability. For example, whereas simplified Atripla tablets are frequently prescribed for HIV treatment in the real world, STARTMRK volunteers were required to take their Truvada in the morning, their Sustiva (or matching placebo) at night and Isentress (or matching placebo) in the morning and at night. “This aspect of the rigorous blinded-study design would have negated any potential advantage of a one-pill once-a-day regimen of efavirenz, tenofovir, and emtricitabine coformulated as Atripla in fostering strict compliance.”

Still, the authors write, “along with efavirenz or boosted protease-inhibitor combinations, raltegravir given with tenofovir/emtricitabine can be considered among the preferred agents for long-term antiretroviral therapy of treatment-naive HIV-infected patients.”

The Friends of AIDS Foundation is dedicated to enhancing the quality of life for HIV positive individuals and empowering people to make healthy choices to prevent the spread of the HIV virus. To learn more about The Friends of AIDS Foundation, please visit: http://www.friendsofaids.org.

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