Once-daily raltegravir found inferior to twice-daily dosing

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Once-daily dosing of the integrase inhibitor raltegravir (Isentress) was found to be inferior to twice-daily dosing for treatment-naive patients in the QDMRK study, even though most people receiving either dose were able to suppress HIV to an undetectable level, researchers reported on Wednesday at the Eighteenth Conference on Retroviruses and Opportunistic Infections (CROI), taking place this week in Boston.

Raltegravir taken every 12 hours has been shown to be a potent component of antiretroviral therapy for both treatment-experienced individuals and those starting therapy for the first time. But twice-daily dosing makes raltegravir less attractive than some other popular first-line treatment options. More frequent dosing is less convenient and may increase the likelihood of poor adherence.

Joseph Eron from the University of North Carolina at Chapel Hill presented findings from QDMRK, a multi-centre phase 3 clinical trial comparing two raltegravir dosing schedules.


concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.


data safety monitoring board (DSMB)

An independent committee of clinical research experts that reviews data not available to the study team while a clinical trial is in progress to ensure that participants are not exposed to undue risks. A DSMB can recommend that the study be stopped if the intervention is not effective, is causing harm to participants or the study is not likely to serve its scientific purpose. Also known as an Independent Data Monitoring Committee (IDMC).

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

The study enrolled 770 previously untreated participants. They were randomly assigned to take raltegravir at doses of either 800mg once daily or 400mg twice daily, both taken in combination with the fixed-dose tenofovir/emtricitabine coformulation (Truvada).

Patient characteristics were similar in the two study arms. Most participants were men and the median age was 38 years. The mean viral load was approximately 69,000 copies/ml and 40% had HIV RNA levels above 100,000 copies/ml. The average CD4 T-cell count was just under 300 cells/mm3, but one-quarter had counts below 200 cells/mm3. Participants had no documented resistance to tenofovir or emtricitabine at baseline.

Due to concerns that once-daily dosing might not be as effective as twice-daily, eight-week data from a "vanguard" group of about 150 patients were analysed before enrolling additional participants. A data safety monitoring committee recommended that the trial proceed without changes after that interim review and another at week 24.

In an intent-to-treat analysis at week 48, counting participants who dropped out before this point as treatment failures, 83.2% of patients in the once-daily raltegravir arm achieved undetectable viral load below 50 copies/ml, compared with 88.9% in the twice-daily arm – among the highest response rates ever seen in a randomised HIV treatment trial, Eron noted.

A similar pattern was seen when looking at viral load below 400 copies/ml, with response rates of 88.5 and 93.5%, respectively. CD4 cell gains were similar in the two arms, at 210 and 196 cells/mm3.

The confidence intervals of the 5.7% estimated difference in proportions of patients with viral suppression below 50 copies/ml failed to meet a pre-specified margin of 10% (85% confidence intervals – 10.7 to 0.83), leading the researchers to conclude that once-daily raltegravir was not non-inferior to twice-daily dosing. In fact, Eron explained, the less frequent dose was actually found to be slightly inferior to the approved dose.

Looking at patient subgroups, the difference in response rates was more pronounced amongst those with high baseline viral load above 100,000 copies/ml. In group, 74.3% receiving once-daily raltegravir and 84.2% taking twice-daily raltegravir reached a viral load below 50 copies/ml, a difference of 9.9%. But even amongst people who started with a lower viral load, twice-daily dosing worked better (89.1 vs 91.9%, respectively), with a difference of 2.7%.

More participants experienced virological failure (defined as HIV RNA above 50 copies/ml at week 24 or viral rebound following suppression) in the once-daily raltegravir arm compared with twice-daily dosing (13.9 vs 9.0%, respectively). A time-to-loss-of-virological-response (TLOVR) analysis also favored the twice-daily schedule.

More people who experienced treatment failure in the once-daily group had evidence of resistance to either raltegravir and emtricitabine or emtricitabine alone; no patients failing treatment in either arm showed resistance to tenofovir.

Both raltegravir dosing schedules were well-tolerated. Very few people in either arm (less than 1%) experienced severe drug-related adverse events, and about 1% in both groups dropped out due to adverse events.

Looking at raltegravir levels in the blood, once-daily dosing produced a higher overall concentration (area under the curve) and maximum concentration, but the minimum or trough concentration between doses fell much lower compared with twice-daily dosing.

Based on these findings, the data monitoring committee recommended that the trial be halted at 48 weeks.

"Both once-daily and twice-daily raltegravir in combination with [tenofovir/emtricitabine] achieved high virologic response rates and similar immunologic effects," the QDMRK researchers concluded. "However, once-daily was inferior in virologic efficacy as compared to twice-daily raltegravir."

Abstracts and webcast

You can view the abstracts from this research on the official conference website:

Abstract 150LB: http://www.retroconference.org/2011/Abstracts/42603.htm

You can also watch a webcast of the presentations made at this conference session.

Webcast from New HIV and HCV Antiviral Agents, Prevention, and ARV Strategies.

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Eron J et al. 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, Boston, abstract 150LB, 2011.