Results from a Phase 3 clinical trial indicate that once-daily administration of the drug Isentress is not as effective as twice-daily administration.

“The results of this study showed that 800 mg [of Isentress] given once daily in combination therapy was inferior to 400 mg [of Isentress] twice daily in combination therapy,” said Robert Consalvo, global director of communications at U.S. pharmaceutical company Merck, which sponsored the study.

“Given the superior efficacy of 400 mg [of Isentress] twice daily, patients are recommended to take it twice daily in combination therapy in accordance with the approved product labeling. Once-daily [Isentress] is not recommended for any patients,” he added.

Isentress (raltegravir) is the first HIV integrase inhibitor approved by the U.S. Food and Drug Administration (FDA). Currently it is prescribed as a twice-daily dose of 400 mg each, in combination with other antiretrovirals as part of highly active antiretroviral therapy.

In recent years, the FDA has approved once-daily rather than twice-daily dosages of several antiretrovirals. For example, the protease inhibitor Prezista (darunavir) was approved in a once-daily dosage in 2008, two years after the drug’s initial approval by the FDA.

According to the study authors, once-daily dosing is more convenient and might promote better adherence to antiretroviral regimens. Better adherence allows for slower disease progression and helps prevent the development of drug-resistant HIV strains.

In this Phase 3 trial, researchers investigated the efficacy of once-daily Isentress versus twice-daily Isentress, both in combination with Truvada (emtricitabine/tenofovir).

The study included 775 adults with HIV who had not previously been treated. All participants had viral loads (amount of HIV in the blood) of more than 5,000 copies per milliliter of blood at the start of the study. Most participants were male (80 percent) and Caucasian (71 percent). The median participant age was 38 years old.

Prior to treatment, 39 percent of study participants had viral loads of more than 100,000 copies per milliliter blood. Additionally, 24 percent of participants had CD4 (white blood cell) counts of less than 200 cells per microliter of blood.

Half of the study participants were randomly assigned to take Isentress once daily, 800 mg every 24 hours. The other half were assigned to take Isentress twice daily, 400 mg every 12 hours.

Results showed that after 48 weeks, 83 percent of study participants in the once-daily group and 89 percent of participants in the twice-daily group successfully achieved undetectable viral loads. The difference was large enough that once-daily Isentress was not considered equivalent in efficacy to twice-daily dosing.

In addition, participants in the once-daily group took longer to achieve undetectable viral loads and were more likely to experience treatment failure than those in the twice-daily group (14 percent of participants versus 9 percent).

The average increase in participant CD4 cell counts at 48 weeks was 210 cells per microliter of blood for the once-daily group and 196 cells per microliter of blood for the twice-daily group. The difference was not considered statistically significant.

Serious side effects were reported by 7 percent of participants in the once-daily group and 10 percent of participants in the twice-daily group. The most common side effects were diarrhea, upper respiratory tract infection, headache, bronchitis, depression, sinusitis, influenza, vomiting, back pain, and high blood pressure.

Overall, 13 percent of the study participants in the once-daily Isentress group and 8 percent of participants in the twice-daily Isentress group discontinued the drug due to side effects or other reasons.

For more information, please see the study in The Lancet (abstract).