Raltegravir (Isentress) with Optimized Background Therapy for Drug-resistant HIV Infection: BENCHMRK 48-week Results

Results from the twin BENCHMRK trials, which evaluated 48 weeks of therapy with raltegravir (Isentress), the only FDA-approved integrase inhibitor, were published in the current issue of The New England Journal of Medicine (July 24, 2008).

The trial data showed that raltegravir, which is active against HIV that is resistant to older antiretroviral drugs, provided significantly greater reductions in viral load and increases in CD4 cell counts compared with placebo in treatment-experienced patients.

Preliminary data from these trials were previously presented by Roy Steigbigel and David Cooper and colleagues at the 14th Conference on Retroviruses and Opportunistic Infections in February 2007 (abstracts 105aLB and 105bLB) and by Princy Kumar and colleagues at the 2007 European AIDS Conference in Madrid (abstract P7.2/06).

The researchers conducted 2 identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients with triple-class drug-resistant HIV who had experience antiretroviral treatment failure. Participants were randomly assigned to receive raltegravir or placebo in a 2:1 ratio for 48 weeks.

Results

• In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug.

• 17 of these 699 patients (2.4%) discontinued the study before week 16.

• Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%).

• The results of the 2 trials were consistent.

• At week 16, counting non-completion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV RNA below 400 copies/mL, compared with 99 of 236 placebo recipients (41.9%)(P < 0.001).

• At week 16, 61.8% of raltegravir recipients and 34.7% of placebo recipients achieved HIV RNA suppression below 50 copies/mL (P < 0.001).

• At week 48, the proportions with HIV RNA below 50 copies/mL were 62.1% versus 32.9%, respectively (P < 0.001).

• The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups.

• Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients.

Based on their findings, the study authors concluded, "In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks."

Like other new anti-HIV drugs in development that work through novel mechanisms of action, raltegravir as part of an optimized combination regimen offers great promise for patients with HIV that is resistant to standard therapies.

The full text of the BENCHMRK article is available free on The New England Journal of Medicine website.

State University of New York at Stony Brook, Stony Brook; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney; Georgetown University Medical Center, Washington, DC; University of North Carolina, Chapel Hill, NC; Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Aaron Diamond Research Center, Rockefeller University, New York, NY; University of Toronto, Toronto, Canada; Emory University School of Medicine, Atlanta, GA; University of Barcelona, Barcelona, Spain; University of Bonn, Bonn, Germany; Hospital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France; Hospital Bichat-Claude Bernard, Paris, France; San Raffaele Scientific Institute, Milan, Italy; Hospital Germans Trias i Pujol, Fundación Irsicaixa, Barcelona, Spain; Merck Research Laboratories, North Wales, PA.

Analysis of Resistance

In another analysis reported in the same issue, the BENCHMRK investigators evaluated factors associated with response and the development of viral resistance in the 2 trials according to baseline prognostic factors. Genotyping of the HIV integrase gene was performed in raltegravir recipients who experienced virological failure.

The researchers found that virological responses to raltegravir were consistently superior to placebo responses, regardless of demographic characteristics, baseline HIV RNA levels, CD4 cell counts, genotypic or phenotypic resistance test sensitivity scores, and use or nonuse of darunavir (Prezista), enfuvirtide (Fuzeon; T-20), or both as part of the optimized background regimen.

Among patients in the 2 studies combined who started both darunavir and enfuvirtide for the first time, 89% of raltegravir recipients and 68% of placebo recipients achieved HIV RNA suppression below 50 copies/mL. Among those starting darunavir (without enfuvirtide), the corresponding rates were 69% for raltegravir recipients and 47% for placebo recipients; among those starting enfuvirtide (without darunavir), the rates were 80% and 57%, respectively.

At 48 weeks, 105 of the 462 raltegravir recipients (23%) had experienced virological failure; viral genotyping was performed for 94 of these patients. Integrase mutations known to be associated with raltegravir resistance arose during treatment in 64 patients (68%); 48 of these 64 (75%) had 2 or more resistance-associated mutations. The prevalence of resistance mutations was lower among patients who started 2 or more other active drugs in addition to raltegravir, compared with those who had no other new active drugs in their background regimen (33% vs 78%).

The study authors concluded that, "When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score."

Editorial

In an accompanying editorial, Diane Havlir of the University of California at San Francisco put the BENCHMRK findings into perspective as raltegravir moves out of the drug development pipeline and into routine clinical use.

For over a decade, she wrote, "we have approached the treatment of drug-resistant HIV as a Sisyphean task, using a strategy that we knew from the start was doomed to fail -- the addition of a single new agent to an ailing regimen. This approach was based not on ignorance but on the lack of new classes of antiretroviral agents."

But this has recently changed, with the near-simultaneous availability of the first drugs in 2 novel classes, raltegravir and the CCR5 antagonist maraviroc (Selzentry).

Commenting on Cooper's findings, Havlir noted that the high-end responses seen in patients who added darunavir and enfuvirtide for the first time along with raltegravir "could potentially be even greater when patients are candidates for the CCR5 inhibitor maraviroc."

But, she emphasized, even though about half the patients who did not also start one of these new drugs still responded to raltegravir, this "should not encourage the sole addition of raltegravir to the regimen of a patient with multiclass-resistant HIV, which could lead to rapid development of drug resistance."

"What do these results mean for clinical practice?" Havlir asked. "The results of the BENCHMRK studies usher in a new era for HIV therapy -- the expectation that combination regimens involving new agents can suppress even the most drug-resistant HIV."

"It is crucial that new HIV agents are used wisely to maximize benefit and minimize resistance," she continued. "It is also important to rethink our current HIV treatment strategies and to extend research on these new agents in other populations, such as patients infected with HIV who have never been treated."

Finally, she wrote, "Given the unmet treatment needs in the global HIV epidemic, it is further incumbent on researchers, policymakers, and advocacy groups to evaluate the optimal use of new agents in low- and middle-income populations and to work toward making the drugs available for both children and adults."

7/25/08

References

RT Steigbigel, DA Cooper, PN Kumar, and others (BENCHMRK Study Teams). Raltegravir with optimized background therapy for resistant HIV-1 infection. New England Journal of Medicine 359(4): 339-354. July 24, 2008.
Full text.

DA Cooper, RT Steigbigel, JM Gatell, and others (BENCHMRK Study Teams). Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. New England Journal of Medicine 359(4): 355-365. July 24, 2008.
Full text.

DV Havlir. HIV integrase inhibitors -- out of the pipeline and into the clinic. New England Journal of Medicine 359(4): 416-418. July 24, 2008.
Full text.