STARTMRK Trial Shows Raltegravir (Isentress) Works as Well as Efavirenz (Sustiva) in Treatment-naive HIV Patients

The first approved integrase inhibitor, raltegravir (Isentress), suppressed HIV viral load as well as efavirenz (Sustiva) over 48 weeks in the STARTMRK trial, a Phase 3 study of previously untreated patients. Participants taking raltegravir, however, experienced fewer drug-related adverse events.

As reported in the August 3, 2009 advance online edition of The Lancet, STARTMRK (sponsored by Merck) enrolled 566 participants from 67 research centers on 5 continents between September 2006 and June 2008.

Eligible patients had HIV RNA > 5000 copies/mL and no evidence of baseline resistance to efavirenz, tenofovir (Viread, also in the Truvada and Atripla coformulations), or emtricitabine (Emtriva). At baseline, 53% patients had viral load < 100,000 copies/mL and 47% had a CD4 count of 200 cells/mm³ or less.

Participants were randomly assigned in a 1:1 ratio to receive either 400 mg raltegravir twice-daily or 600 mg efavirenz once-daily, both in combination with 300/200 mg tenofovir/emtricitabine once-daily. To make sure the study was blinded, patients in the raltegravir arm also received placebo tablets matching efavirenz, while those in the efavirenz arm received raltegravir-matching placebos.

The primary efficacy endpoint was achievement of HIV RNA < 50 copies/mL at week 48, with a margin of non-inferiority of 12%.

Results

• In a 48-week non-completion = failure analysis, 86.1% of patients in the raltegravir arm and 81.9% in the efavirenz arm achieved HIV RNA < 50 copies/mL.
• The difference in efficacy was 4.2%, thereby meeting the criteria for raltegravir non-inferiority.
• The average time to achieve viral suppression, however, was significantly shorter for patients in the raltegravir arm compared with the efavirenz arm (P < 0.0001).
• Mean changes in CD4 count from baseline to week 48 were 189 cells/mm³ in the raltegravir arm and 163 cells/mm³ in the efavirenz arm (P = 0.0184)
• Patients in the raltegravir arm experienced significantly fewer drug-related clinical adverse events -- including central nervous system symptoms -- than those taking efavirenz (44.1% vs 77.0%; P < 0.0001).
• Serious drug-related clinical adverse events occurred in less than 2% of patients in both arms.
• Fewer laboratory-associated adverse events were recorded in the raltegravir arm compared with the efavirenz arm, but the difference did not reach statistical significance.
• Patients taking raltegravir experienced small increases in total cholesterol, LDL ("bad") cholesterol, HDL ("good") cholesterol, and triglycerides, but changes were significantly higher for efavirenz recipients.

Based on these findings, the study authors concluded, "Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48."

"Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients," they continued.

In their discussion, the researchers explained that non-inferiority of raltegravir "was not solely due to the higher number of discontinuations in the efavirenz group than in the raltegravir group."

"Both regimens had consistent efficacy across all baseline prognostic and stratification factors, including patients with high viral loads or low CD4 cell counts," they added

They also noted that more patients taking raltegravir reached undetectable HIV RNA levels by weeks 2-16 (studies typically do not report response prior to 24 weeks), but the clinical significance of this early response is not clear.

Virological failure was rare in both treatment groups, the researchers stated. Of the 8 patients in the raltegravir arm who experienced virological failure with > 400 copies/mL and an HIV integrase gene that could be analyzed, half had mutations known to confer raltegravir resistance.

A smaller Phase 2 study comparing similar regimens (but using lamivudine instead of emtricitabine) found that both raltegravir and efavirenz produced sustained viral suppression though 144 weeks (78% vs 76% < 50 copies/mL, respectively).

Emory University School of Medicine, Atlanta, GA; Orlando Immunology Center, Orlando, FL; Universita Vita-Salute San Raffaele, Milan, Italy; University of California at Davis, Sacramento, CA,; Centro de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; Northstar Medical Center, University of Illinois at Chicago, Chicago, IL; Merck Research Laboratories, North Wales, PA.

8/11/09

Reference

JL Lennox, E DeJesus, A Lazzarin, and others (for the STARTMRK investigators). Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. The Lancet. August 3, 2009 (Epub ahead of print).