Merck’s integrase inhibitor Isentress (raltegravir) continues to perform well, compared with Sustiva (efavirenz), after four years in people living with HIV starting therapy for the first time in the company’s STARTMRK clinical trial. For those who do develop HIV drug resistance to Isentress, the experimental integrase inhibitor dolutegravir (S/GSK-572) showed promise as a second-line treatment option in ViiV Healthcare’s VIKING study. Both sets of study conclusions were reported Thursday, October 13, at the 13th European AIDS Conference in Belgrade, Serbia. 

After 192 weeks of treatment involving Isentress plus Truvada (tenofovir plus emtricitabine), according to the strictest data analysis performed by Jürgen Rockstroh, MD, of the University of Bonn in Bonn-Venusberg, Germany, and his STARTMRK colleagues, about 76 percent of Isentress-treated patients had undetectable viral loads (below 50 copies), compared with 67 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. 

As for patients with HIV resistance to Isentress—and, most likely, to Gilead’s experimental integrase inhibitor elvitegravir—dolutegravir reduced viral load to below 50 copies in about 75 percent of patients treated for 24 weeks. These findings, which come from a second group of patients using 50 milligrams (mg) of the drug twice daily, are superior to those of an initial group of patients in the VIKING study involving once-daily dosing of the drug. Compared with those in VIKING cohort II, undetectable viral loads after 24 weeks were documented in only 41 percent of those in VIKING cohort I. 

Three-year follow-up data from STARTMRK were recently published in the October 15 issue of Clinical Infectious Diseases. The four-year follow-up data are similar, in that they conclude that a regimen of twice-daily Isentress plus once-daily Truvada appears to work just as well as once-daily Sustiva plus Truvada—usually taken together as Atripla—but with fewer blood lipid problems. 

Of note, the four-year follow-up data from STARTMRK suggest that Isentress-based therapy may have an immunologic edge over Sustiva-based treatment. According to the data shared by Rockstroh’s group in Belgrade, CD4 counts increased, on average, by 360 cells in the Isentress group, compared with 300 cells in the Sustiva group. But here, too, a statistical comparison to determine superiority was not possible. 

Preliminary 11-day study results from VIKING cohort II were reported at the 18th Conference on Retroviruses and Opportunistic Infections in Boston, earlier this year, with 24-week follow-up data reported by Vincent Soriano, MD, of Hospital King Carlos in Madrid and his colleagues in Belgrade. 

Compared with the lackluster virologic response using once-daily dolutegravir documented in VIKING cohort 1, Soriano confirmed that twice-daily dosing made a significant difference. Based on these results, ViiV’s Phase III clinical trial program will further explore the safety and efficacy of twice-daily dolutegravir in people living with HIV with evidence of resistance to Isentress and elvitegravir. For patients starting therapy for the first time or with no integrase inhibitor experience, once-daily dosing continues to be a possibility and is being evaluated in clinical trials. 

Data from VIKING cohort II suggest that treatment responses to dolutegravir, even when twice-daily dosing is used, will depend on the actual integrase mutations that occur during treatment with first-generation integrase inhibitors. And much like other experimental agents that show promise against drug-resistant HIV, the effectiveness of dolutegravir will also depend on the number of active antiretrovirals—HIV drugs to which the virus is not resistant—that can be combined with it.