Once-daily Raltegravir Found Less Effective than Twice-Daily Dosing

In treatment-naive HIV patients the integrase inhibitor raltegravir (Isentress) taken once-daily was inferior to twice-daily dosing, according to findings from the QDMRK study presented this week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston. The difference in efficacy was especially pronounced among people with low baseline viral load.

Current U.S. treatment guidelines include twice-daily raltegravir as a preferred component of first-line antiretroviral therapy (ART). But many people with HIV and their clinicians favor once-daily regimens, which may enable better adherence.

Joseph Eron from the University of North Carolina at Chapel Hill and fellow investigators conducted the QDMRK trial to compare the efficacy and safety of once-daily vs twice-daily raltegravir. It was designed as a non-inferiority study with a pre-specified margin of 10%.

Pharmacokinetic and in vitro data from previous studies suggest that once-daily raltegravir dosing might be an effective alternative to twice-daily dosing, the investigators noted as background.

QDMRK enrolled 770 treatment-naive HIV positive individuals and randomly assigned them (1:1) to receive raltegravir at doses of 800 mg once-daily or 400 mg twice-daily, both in combination with fixed-dose tenofovir/emtricitabine (Truvada).

Most participants (roughly 80%) were men, more than two-thirds were white, the median age was 38 years, and 7% were coinfected with hepatitis B or C. The mean pre-treatment HIV RNA level was approximately 69,000 copies/mL, and 40% of patients had viral load above 100,000 copies/mL. The average CD4 T-cell count was about 280 cells/mm3, but one-quarter had fewer than 200 cells/mm3. Participants had no documented resistance to tenofovir or emtricitabine at study entry.

Data from a "vanguard" group of about 150 patients was analyzed at week 8, while enrollment was paused. Another interim review was done at week 24, and a data safety monitoring committee recommended that the trial proceed without modification. The primary endpoint was virological suppression at week 48, with a secondary endpoint analysis planned for week 96.

Results

• At 48 weeks, 83.2% of participants in the once-daily raltegravir arm and 88.9% in the twice-daily arm achieved HIV RNA < 50 copies/mL in an intent-to-treat analysis.
• 88.5% and 93.5%, respectively, achieved viral load < 400 copies/mL.
• The difference in rates of viral suppression < 50 copies/mL was 5.7%, but since the upper bound of the confidence interval was 10.7%, the researchers concluded that once-daily dosing was not non-inferior based on the pre-set 10% margin.
• The lower bound of the confidence interval was 0.83, leading researchers to conclude that once-daily raltegravir was actually slightly inferior to twice-daily.
• The divergence in response rates (< 50 copies/mL) was more pronounced among people with baseline viral load > 100,000 copies/mL: 74.3% in the once-daily arm and 84.2% in the twice-daily arm, a difference of 9.9%.
• A significant difference was still seen, however, among people with low baseline viral load: 89.1% vs 91.9%, respectively, a difference of 2.7%.
• There was also a larger disparity in response among people with lower CD4 counts:
  • 200 cells/mm³ or less: 70.8% vs 80.8%, a difference of 10.0%;
  • > 200 cells/mm³: 87.0% vs 91.6%, a difference of 4.6%.
• CD4 cell increases were similar in the once-daily and twice-daily arms, at 210 and 196 cells/mm³, respectively.
• More people in the once-daily raltegravir arm experienced virological failure than in the twice-daily arm, 13.9% vs 9.0%, respectively.
• Drug-resistance patterns showed some differences between groups:
  • 9 people in the once-daily raltegravir arm and 2 in the twice-daily arm had both integrase and emtricitabine resistance mutations;
  • 11 and 4, respectively, were resistance to only emtricitabine;
  • 7 people in both arms showed no evidence of resistance.
• The safety of once-daily and twice-daily raltegravir was similar:
  • No one in either study arm died;
  • 1 patient (0.3%) in the once-daily arm and 2 people (0.5%) in the twice-daily arm experienced drug-related serious adverse events;
  • 2 people (0.5%) in each arm discontinued treatment due to drug-related adverse events.
• Pharmacokinetic parameters also differed between the once-daily and twice-daily arms:
  • Total raltegravir drug exposure (area under the curve) was more than twice as high in the once-daily arm;
  • Maximum raltegravir concentration (Cmax) was about 4 times higher;
  • Minimum or trough concentration, in contrast, was more than 6 times lower.

"Despite high virologic response rates in both [once-daily] and [twice-daily] arms, [once-daily] raltegravir was inferior in virologic efficacy compared to [twice-daily] raltegravir," the researchers concluded.

Based on these findings, the data monitoring committee recommended that the trial should be stopped after the 48 week analysis.

"No matter how you subdivided [study participants]," Eron said at a press conference following his presentation, "the numbers always favored twice-daily."

Investigator affiliations: Univ of North Carolina at Chapel Hill, Chapel, NC; Univ of Bonn, Germany; Ctr Hosp Univ Montpellier, France; Univ of Guadalajara, Mexico; Ctr de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; Merck Research Labs, North Wales, PA.

Reference

J Eron, J Rockstroh, J Reynes, and others. QDMRK, a Phase III Study of the Safety and Efficacy of Once Daily vs Twice Daily RAL in Combination Therapy for Treatment-naive HIV-infected Patients. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 150LB.