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PRIORITY PRESS - 9th International Congress on Drug Therapy in HIV Infection (HIV9)

Glasgow, Scotland / November 9-13, 2008

Dr. David Hardy, Director Divison of Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, California, detailed the 96-week data from the randomized, double-blind placebo-controlled phase IIb and III ‘Maraviroc vs. Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients’ (MOTIVATE 1 and MOTIVATE 2) studies. He emphasized that with any new HIV medication which has a novel mechanism of action, it is crucial to obtain long-term data so as to understand the durability of its efficacy and to determine its toxicity and long-term side effects.

Long-term Viral Suppression

As the first approved CC chemokine receptor 5 (CCR5) inhibitor for treatment-experienced patients, maraviroc has antiviral activity directed specifically against CCR5-tropic HIV-1. Dr. Hardy recalled that in a primary analysis at 48 weeks, in both MOTIVATE 1 (with 601 patients in the US and Canada) and MOTIVATE 2 (474 patients in Europe, Australia and the US), maraviroc once daily or twice daily plus optimized background therapy (OBT) based on treatment history and drug-resistance testing demonstrated “significantly greater virological and immunological efficacy and a similar safety profile compared to placebo plus OBT.”

Those findings were confirmed and reinforced by the 96-week data, he told the audience. “Maraviroc plus OBT results in durable viral suppression through 96 weeks in treatment-experienced patients with R5 HIV-1, with the vast majority (87%) of patients receiving the drug twice daily who were fully suppressed at week 48 remaining suppressed at week 96.”

Three-arm Trial Design

Outlining the identical design of the MOTIVATE trials, Dr. Hardy explained that it comprised three arms: OBT plus placebo; OBT plus maraviroc 150 mg q.d.; and OBT plus maraviroc 150 mg b.i.d.

To be eligible for inclusion, patients had to be treatment-experienced, with R5 HIV-1 infection only, as confirmed by a co-receptor tropism assay and a plasma HIV-1 RNA level of at least 5000 copies/mL. Patients were ineligible if there was evidence of infection with the X4 virus, which tends to emerge during the later phases of the disease, whereas R5 HIV-1 predominates in the early stages. Further eligibility criteria were a stable pre-study antiretroviral regimen or having received no antiretrovirals for at least four weeks, and resistance to and/or at least six months’ experience with one antiretroviral agent from three classes (or two for protease inhibitors).

At week 48, nearly half of those receiving the active treatment (43.2% of those with once-daily dosing and 45.5% of those receiving twice-daily dosing) had fewer than 50 copies/mL of HIV-1 RNA—“an undetectable biological load.” Significantly more patients (P<0.001) benefited from the active drug than those given placebo who reached the same biological efficacy point (16.7%). At this stage, when the last patient to be randomized reached week 48, all patients were unblinded and given the option to continue on open-label maraviroc.

96-week End Point Analyses

Two analyses were conducted to characterize the week 96 combined MOTIVATE 1 and 2 end points, Dr. Hardy reported. An efficacy analysis included patients receiving maraviroc once or twice daily who had undetectable viral loads (HIV-1 RNA <50 copies/mL) at week 48 and were followed until week 96. A safety analysis included all available blinded data. It did not include data on open-label treatment.

At 96 weeks, Dr. Hardy reported, “The suppression of virus remained persistently good,” as 41.3% of those with once-daily dosing and 38.9% of those receiving twice-daily dosing had <50 copies/mL of HIV-1 RNA, vs. 7.2% with placebo. Non-completers were categorized as failures.

The clinical outcomes at week 96 were that among those patients who, at week 48, had <50 copies/mL of HIV-1 RNA, 81.4% of the 172 recipients of once-daily blinded therapy and open-label maraviroc and 86.7% of those on twice-daily therapy were still at that level, with 10.5% and 9.9%, respectively, having higher HIV-1 RNA counts, of 50 to 400 copies/mL. Only 1.2% and 0.6% discontinued due to lack of efficacy, defined as HIV-1 RNA levels of at least three times the HIV-1 RNA baseline level. This analysis did not include patients who stopped active treatment for non-efficacy reasons (four because of adverse events, eight lost to follow-up and four for other reasons).

Longer Exposure with Active Treatment

Discussing the duration of long exposure to study agent, Dr. Hardy pointed out that there were significant differences —20 weeks with placebo, 48 weeks in both active agent arms— because of the higher failure rate in the placebo arm. “At the end of blinded therapy, there is almost four times as long exposure with both once-daily and twice-daily maraviroc than patients on placebo. ”

Comparing the incidence of malignancies at week 48 and at the end of blinded treatment, Dr. Hardy mentioned there was nothing to indicate an increased detection of malignancies in either maraviroc arm but there were more malignancies with placebo.

Regarding malignancies specifically related to an infection, the most common was anal carcinoma, followed by Kaposi’s sarcoma and lymphoma. There was no particular non-infection related neoplasm associated with maraviroc that differed from placebo. Nor was there any evidence at the end of blinded therapy that the agent was associated with increased risk of opportunistic or category C events (AIDS-defining infections or diseases).

No New Safety Signals

Pooled analyses revealed no new or unique safety signals. Category C events, malignancies and liver function test abnormalities occurred with similar frequency among treatment groups even when not adjusted for the longer duration of exposure in the maraviroc groups, and the incidence of those events declined after week 48.

At week 48, there had been concern about a higher incidence of nasopharyngitis and upper respiratory tract infections in recipients of active drug than with placebo but when incidence was adjusted for exposure, it was no higher with the active agent.

More patients receiving maraviroc maintained HIV-1 suppression to <400 and <50 copies/mL until week 96 than those taking placebo. Fewer maraviroc patients experienced virological failure between weeks 48 and 96 than placebo recipients. Incidence of serious adverse events, category C events and malignancies were similar among treatment arms even when unadjusted for exposure, which was significantly greater in each of the maraviroc arms than the placebo arm.

Summary

Dr. Hardy emphasized that maraviroc plus OBT had been shown to result in “durable viral suppression” for up to 96 weeks in treatment-experienced patients with R5 HIV-1. As many as 87% of patients receiving twice-daily dosing who had been fully suppressed at week 48 remained suppressed at week 96.

Dr. Hardy reminded delegates that maraviroc had been shown at week 48 to improve CD4 + cell counts significantly. The count at week 96 was different, he noted analysis of this had not yet been completed.

Commenting on the role of CCR5 blockers in antiretroviral therapy, Prof. Juergen Rockstroh, Bonn University, Germany, said they offered “a promising new approach with maraviroc,” and that it had shown to be “extremely well tolerated without any specific safety issues in combination with other antiretroviral therapies.” He added that its positioning into earlier treatment lines of HIV therapy would depend on data from ongoing trials as well as the ease of tropism testing in a clinical setting.

According to Prof. Yves Lévy, Henri-Mondor Hospital, Paris, France, maraviroc might block the migration of CCR5+ cells into tissues. That would increase the number of CD4+ cells in circulation and/or prevent their killing by HIV in tissues.

He concluded “there is a need for interventions which maximize both viral suppression and immune restoration and thus prevent the harmful consequences of chronic immune activation. The preservation of the CD4+ cell through HIV control and enhancing de novo T-cell regeneration would become an additional goal of HIV/AIDS therapy.”