Twice-Daily Raltegravir Preferred for HIV-Naive Patients

Brian Hoyle

March 08, 2011

March 8, 2011 (Boston, Massachusetts) — Raltegravir (Isentress, Merck) is the antiretroviral drug of choice for treatment-naïve HIV-infected patients. Results from the QDMRK trial indicate that twice-daily raltegravir is more effective than once-daily raltegravir, and that twice-daily dosing is well tolerated.

The results were reported here at the 18th Conference on Retroviruses and Opportunistic Infections.

"What the study showed is that the current way we give raltegravir, twice a day, is very effective and well tolerated. The experimental way we tried, the once-daily regimen, while quite active, did not quite measure up to giving the drug twice a day," Joseph Eron, MD, from the University of North Carolina at Chapel Hill, told Medscape Medical News.

"The logic behind the trial is that if you can give a medicine once a day as opposed to twice a day, you are probably going to have better adherence to treatment by the patient," Dr. Eron told Medscape Medical News.

The randomized phase 3 study compared once-daily with twice-daily raltegravir in treatment-naïve HIV-infected patients.

The trial involved 770 HIV-positive treatment-naïve patients who displayed a high viral load (more than 5000 HIV RNA copies/mL) and an absence of resistance to tenofovir or emitricitabine. Patients were randomized to receive either once-daily raltegravir 800 mg (n = 382) or twice-daily raltegravir 400 mg (n = 388). In both treatment groups, raltegravir was administered in combination with a coformulation of tenofovir and emitricitabine.

The primary end point was virological suppression, defined as a reduction in HIV RNA (below 50 copies/mL) and a viral load below detectable levels (below 400 copies/mL) at 48 weeks. CD4 count and various parameters indicative of safety were also determined.

At baseline, 40% and 39% of patients randomized to the once-daily or twice-daily group, respectively, had an HIV RNA viral load exceeding 100,000 copies/mL.

At 48 weeks, virologic failure (nonresponse or rebound) occurred in 88 patients — in 53 of 382 patients (13.9%) in the once-daily group and in 35 of 388 (9.0%) patients in the twice-daily group.

Resistance developed in 9 patients in the once-daily group and in 2 patients in the twice-daily group. Serious adverse events and discontinued treatment were similar in both groups.

The overall rates of suppression of HIV to below 50 copies/mL were impressive in both groups, Dr. Eron said; they were 83.2% for once-daily treatment and 88.9% for twice-daily treatment.

In patients whose baseline viral loads were 100,000 copies/mL or less, the overall efficacy rates were similar for the once-daily group (89.1%; 205 of 230 patients) and twice-daily group (91.9%; 215 of 234 patients).

"The 92% of patients who received raltegravir twice a day and who were suppressed below the level of detection at 48 weeks is one of the highest numbers we've seen in any randomized clinical trial," Dr. Eron told Medscape Medical News.

However, while the responses in each group were similar, the difference in the response was statistically large enough so that the once-daily regimen did not meet the study goal (noninferiority to twice-daily raltegravir), and was actually slightly inferior, Dr. Eron explained.

In patients with a baseline viral load exceeding 100,000 copies/mL, the difference in the treatment groups was much more apparent, he added. The suppression efficacy for once-daily treatment was only 74.3% (113 of 152), whereas it was 84.2% (128 of 152) for twice-daily treatment.

"Patients who had a very high viral load were more likely to have virologic failure when receiving the once-a-day dose. But, even when you looked at people with lower viral loads at the start, there was a numeric difference [between groups]. We looked at the data many different ways, and there was always a numeric difference in favor of the approved twice-a-day regimen," Dr. Eron told Medscape Medical News.

"I was surprised at the results of this study," said Bernard Hirschel, MD, from the Hopitaux Universitaires de Genève, in Geneva, Switzerland, who moderated the session at which Dr. Eron presented the QDMRK results.

"I thought that it would be a sure bet that once-daily raltegravir would be noninferior, for 2 reasons: in phase 2 studies, inferior doses had appeared just as effective as 400 mg [twice daily]; and low trough levels were not linked to virological failure. However, QDMRK shows that such inferences are not enough. This is why we do these trials," Dr. Hirschel told Medscape Medical News.

Dr. Eron reports a financial relationship with Bristol-Myers Squibb, GlaxoSmithKline, Merck, Tibotec, and ViiV Healthcare. Dr. Hirschel has disclosed no relevant financial relationships.

18th Conference on Retroviruses and Opportunistic Infections (CROI): Abstract  150LB. Presented March 2, 2011.

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