CCR5 Antagonist Maraviroc (Selzentry) Suppresses HIV in Treatment-experienced Patients with Drug-resistant Virus

By Liz Highleyman

Maraviroc (Selzentry) Tablet

The first-in-class CCR5 antagonist maraviroc (Selzentry) received U.S. Food and Drug Administration (FDA) approval in August 2007 for use in combination with other antiretroviral agents by treatment-experienced patients with drug-resistant HIV.

CCR5 antagonists work by blocking one of the 2 co-receptors (CCR5 and CXCR4) that HIV uses, along with the CD4 surface receptor, to enter cells.

The drug's approval was based on data from the pivotal MOTIVATE (Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients) 1 and 2 trials. Results from these studies have been presented at scientific conferences over the past 2 years, and now appear in print in the October 2, 2008 issue of the New England Journal of Medicine.

These twin double-blind, placebo-controlled Phase 3 studies included patients with exclusively CCR5-tropic HIV-1 (only virus that uses the CCR5 co-receptor, rather than CXCR4 or both). MOTIVATE 1 was conducted in the U.S. and Canada, while MOTIVATE 2 enrolled participants in the U.S., Europe, and Australia.

HIV-1 interacts with a cell-surface receptor, primarily CD4, and through conformational changes becomes more closely associated with the cell through interactions with other cell-surface molecules, such as the chemokine receptors CXCR4 and CCR5.

Participants had been treated with or had resistance to 3 antiretroviral drug classes (nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors) and had a viral load above 5000 copies/mL. At baseline, the mean baseline HIV RNA level was 72,400 copies/mL and the median CD4 count was 169 cells/mm3.

A total of 1049 participants were randomly assigned to antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, all with optimized background therapy (OBT) selected based on treatment history and resistance testing. Safety and efficacy were assessed after 48 weeks.

Results

• At 48 weeks, the mean decline in HIV RNA from baseline was greater with maraviroc than with placebo:

-- MOTIVATE 1:
• once-daily maraviroc + OBT: -1.66 log10 copies/mL;
• twice-daily maraviroc + OBT: -1.82 log10 copies/mL;
• placebo + OBT: -0.80 log10 copies/mL.

-- MOTIVATE 2:
• once-daily maraviroc + OBT: -1.72 log10 copies/mL;
• twice-daily maraviroc + OBT: -1.87 log10 copies/mL;
• placebo + OBT: -0.76 log10 copies/mL.

• More patients receiving maraviroc once or twice daily achieved an HIV RNA level less than 50 copies/mL:

-- MOTIVATE 1:
• once-daily maraviroc + OBT: 42%;
• twice-daily maraviroc + OBT: 47%;
• placebo + OBT: 16%.

-- MOTIVATE 2:
• once-daily maraviroc + OBT: 45%;
• twice-daily maraviroc + OBT: 45%;
• placebo + OBT: 18%.

• The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo:

-- MOTIVATE 1:
• once-daily maraviroc + OBT: +113 cells/mm3;
• twice-daily maraviroc + OBT: +122 cells/mm3;
• placebo + OBT: +54 cells/mm3.

-- MOTIVATE 2:
• once-daily maraviroc + OBT: +122 cells/mm3;
• twice-daily maraviroc + OBT: +128 cells/mm3;
• placebo + OBT: +69 cells/mm3.

• Frequencies of adverse events were similar across all groups.

Based on these findings, the study authors concluded, "Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with [CCR5-tropic] HIV-1 who were receiving OBT."

Weill-Cornell Medical College, New York, NY; Quest Clinical Research and Mount Zion Hospital of the University of California, San Francisco, San Francisco, CA; Centre Hospitalier Universitaire St-Pierre, Brussels, Belgium; Orlando Immunology Center, Orlando, FL; Wojewodzki Szpital Zakazny, Warsaw, Poland; University of South Florida, College of Medicine, Tampa, FL; Fundació Irsicaixa and Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Venhälsan, Karolinska University Hospital, Stockholm, Sweden; Wohlfeiler, Piperato, and Associates, North Miami Beach, FL; Pfizer Global Research and Development, New London, CT and Sandwich, UK.

MOTIVATE Subanalyses

In the same issue, the MOTIVATE investigators reported results from subanalyses of the combined data that were performed to better characterize the efficacy and safety of maraviroc in key subgroups of patients.

The researchers analyzed pooled 48-week data from the 2 studies according to patient sex, race/ethnicity, HIV clade, CCR5 delta-32 genotype, HIV tropism at baseline, viral load at the time of screening, baseline CD4 cell count, number of active drugs in the regimen, use or non-use of enfuvirtide (T-20; Fuzeon), and first use of other selected background agents.

Changes in viral tropism and CD4 count at the time of treatment failure were evaluated. Among patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV), aminotransferase levels were analyzed to monitor for potential liver toxicity.

Results

• Maraviroc + OBT demonstrated a treatment benefit over placebo + OBT in all subgroups, including patients with a low baseline CD4 count, those with a high viral load, and those without other active agents in their OBT.

• However, patients who started another potent new drug in their regimen along with maraviroc gained additional benefit.

• More patients who experienced treatment failure while on maraviroc had CXCR4-tropic HIV at the time of failure.

• However, these patients did not have a larger decrease in CD4 count at the time of failure compared with those taking placebo.

• Analysis of patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects compared with baseline.

The authors of this report concluded that, "Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with [CCR5-tropic] HIV-1 infection who have been treated previously."

Universitätsklinik Köln, Cologne, Germany; Chelsea and Westminster Hospital, London, UK; Istituto di Ricerca e Cura a Carattere Scientifico San Raffaele, Milan, Italy; University Medical Center Utrecht, Utrecht, Netherlands; University of California, San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA; Geneva University Hospital, Geneva, Switzerland; University of Pennsylvania, Philadelphia, PA; University Hospital, Hôtel-Dieu, Medical University, Nantes, France; Clinique Médicale L'Actuel, Montreal, Canada; Southwest Infectious Disease Associates, Dallas, TX; University of Alabama, Birmingham, Birmingham, AL; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Pfizer Global Research and Development, New London, CT and Sandwich, UK.

Editorial

In an accompanying editorial, Rafael Dolin, MD, discussed the challenges of incorporating this new class of antiretroviral agents into clinical practice.

"As a representative of a new class of anti-HIV drugs, maraviroc faces certain challenges unique to its use as well as some challenges it shares with other antiretroviral drugs," he wrote.

The main barrier is that maraviroc may only be used by people with HIV that exclusively uses the CCR5 co-receptor, which necessitates the "logistic and financial burden" of tropism testing.

There is also concern that using a CCR5 inhibitor might select for CXCR4-tropic HIV strains that potentially could be more pathogenic. In these studies, however, patients receiving maraviroc who had CXCR4-tropic HIV at the time of treatment failure still had higher CD4 cell counts than patients in the placebo group, suggesting that more aggressive virus was not selected.

The overall safety profile of maraviroc "appeared to be similar" to that of placebo in these studies -- a reassuring finding since the natural function of CCR5 and the consequences of interfering with it long-term are not yet fully understood.

Given that CCR5-tropic HIV tends to predominate during the earlier stages of infection, drugs like maraviroc might be particularly advantageous for individuals with less advanced disease, and maraviroc is currently undergoing testing in treatment-naive patients.

"The fact that CCR5 inhibitors can prevent entry of HIV-1 may make them particularly attractive for early use -- either orally or perhaps by topical administration, as a microbicide -- as a means of interrupting viral transmission," Dr. Dolin wrote. "Effective therapy early in infection might also interfere with the rapid loss of CCR5+CD4+ T-cells from gut-associated lymphoid tissue, which is a devastating early result of HIV-1 infection."

"The availability of a new class of anti-HIV drugs is a most welcome addition to the armamentarium against the virus," he concluded. "Optimal use is a challenge that will require continued study and vigilance by investigators, clinicians, and patients themselves."

10/03/08

References

RM Gulick, J Lalezari, J Goodrich (for the MOTIVATE Study Teams). Maraviroc for previously treated patients with R5 HIV-1 infection. New England Journal of Medicine 359(14): 1429-1441. October 2, 2008. (Abstract).

G Fätkenheuer, M Nelson, A Lazzarin, and others (for the MOTIVATE 1 and MOTIVATE 2 Study Teams). Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. New England Journal of Medicine 359(14): 1442-1455. October 2, 2008. (Abstract).

R Dolin. A new class of anti-HIV therapy and new challenges. New England Journal of Medicine 359(14): 1509-1511. October 2, 2008.