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Raltegravir (Isentress) Has Durable Antiviral Activity and Remains Well-tolerated after 3 Years

SUMMARY: The first-in-class integrase inhibitor raltegravir (Isentress) continues to demonstrate good antiviral efficacy in heavily treatment-experienced HIV patients, with 42% of study participants maintaining an undetectable viral load, researchers reported at the 47th Annual Meeting of the Infectious Diseases Society of America (IDSA 2009) last weekend in Philadelphia. Even with long-term follow-up, raltegravir was associated with remarkably few side effects.

By Liz Highleyman

The U.S. Food and Drug Administration (FDA) approved raltegravir for treatment-experienced patients in October 2007, and for treatment-naive individuals in July 2009.

Following completion of the randomized portion of the double-blind Phase 2 trial known as Protocol 005, treatment-experienced study participants were given the option to continue to take raltegravir and receive extended follow-up. The trial included patients with about 10 years of prior antiretroviral therapy (ART) and resistance to agents in 3 older antiretroviral drug classes who were experiencing treatment failure on their current regimen.

Participants were initially randomized to receive raltegravir at doses of 200, 400, or 600 mg twice-daily, or else placebo, along with optimized background therapy (OBT) for at least 24 weeks. More than 60% were taking OBT with limited activity due to drug resistance. During the study extension, everyone received open-label 400 mg twice-daily raltegravir.

A total of 133 patients initially received raltegravir and 45 received placebo. Most (about 90%) were men and the median CD4 cell count was around 230 cells/mm3. Since the 3 raltegravir doses all demonstrated efficacy, raltegravir recipients -- including 94 patients (71%) who entered the open-label extension phase -- were combined into a single group for further analysis.


In an intent-to-treat, non-completer = failure analysis, proportions of raltegravir recipients who achieved HIV RNA < 50 copies/mL were as follows:
Week 48: 55%;
Week 96: 48%;
Week 144: 43%.
At 144 weeks, patients who included enfuvirtide (T-20; Fuzeon) in their OBT had a higher rate of response than those who did not:
No enfuvirtide: 39%;
First-time enfuvirtide: 67%;
Enfuvirtide-experienced: 47%.
CD4 cell increases were similar at all time points (96, 104, and 97 cells/mm3, respectively, at 48, 96, and 144 weeks).
Among patients who experienced treatment failure on raltegravir during the double-blind phase, there was no benefit in continuing raltegravir, since most did not have active drugs to construct an OBT regimen.
Among patients who experienced treatment failure while using placebo during the double-blind phase, 32% of those who switched to raltegravir in the open-label phase achieved undetectable viral load.
Overall, raltegravir was generally well-tolerated.
Over the entire study period, just 1.5% of participants experienced serious drug-related adverse events.
5 participants (3%) discontinued therapy due to adverse events.

Based on these findings, the investigators concluded, "In patients with limited treatment options, raltegravir in combination with OBT had potent and durable antiretroviral effect through week 144, and was generally well tolerated."

The researchers noted that the 32% of initial placebo patients who achieved undetectable viral load when they switched to raltegravir during the open-label was lower than the 43% who did so when randomized to raltegravir from the beginning, "underscoring the need of starting raltegravir with active OBT for maximal benefit."

University of Barcelona, Spain; Merck Research Laboratories, North Wales, PA; Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janerio, Brazil; Hôpital Pitié-Salpêtrière, Paris, France; University of North Carolina, Chapel Hill, NC; San Raffaele Science Institute, Milan, Italy; Hôpital Paul Brousse, Villejuif, France; New York University School of Medicine, New York, NY.


JM Gatell, B-Y Nguyen, B Grinsztejn, and others. 144-Week Efficacy & Safety of Raltegravir in Treatment-Experienced Patients. 47th Annual Meeting of the Infectious Diseases Society of America (IDSA 2009). Philadelphia, PA. October 29-November 1, 2009. Abstract 276.


























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