Gulick RM, Lalezari J, Goodrich J, et al. N Engl J Med. 2008;359(14):1429–1441
PURPOSE OF THE STUDY. Although there are now >20 anti-HIV medications, new agents are still needed. HIV drug resistance is highly prevalent and 15% of newly infected patients in the United States have drug-resistant virus. In addition, enhanced safety and tolerability and improved convenience would enhance adherence to antiretroviral regimens. HIV uses 1 of 2 chemokine receptors, in addition to CD4, to gain entry into a cell, chemokine receptor 5 (CCR5) and α-chemokine receptor 4 (CXCR4). HIV that uses CCR5 is the primary type of virus that is transmitted through sexual or perinatal exposure. CCR5 antagonists are a new class of antiretroviral agents. The purpose of this study was to evaluate a CCR5 antagonist, maraviroc, in the treatment of HIV-infected adults.
STUDY POPULATION. Two double-blind, placebo-controlled studies were conducted. More than 1000 patients were randomly assigned to receive either maraviroc or placebo in combination with investigator-chosen optimized background therapy. Most patients were resistant to multiple classes of antiretroviral agents; mean baseline viral loads were >72 000 copies per mL, and median CD4+ cell counts were 169 cells per mm3.
METHODS. Subjects were assigned to receive maraviroc or placebo in addition to optimized background therapy based on treatment history and drug resistance testing. Safety and efficacy were assessed after 48 weeks.
RESULTS. The demographic and baseline characteristics of patients were similar between the 2 study groups (placebo and active drug). A significantly greater proportion of individuals receiving placebo discontinued treatment, primarily because of lack of efficacy. The primary end point of the study, mean change in plasma levels of HIV RNA, was substantially greater for maraviroc-treated patients than placebo-treated patients (−1.82 log10 copies per mL in the maraviroc-treated group, compared with −1.079 log10 copies per mL in the placebo-treated group). Secondary end points included the proportion of subjects who achieved undetectable viral loads (<50 copies per mL of plasma) at 48 weeks. Forty-seven percent of individuals receiving maraviroc twice daily achieved viral suppression, compared with ∼18% of placebo-treated patients. Finally, the improvement in circulating CD4+ T-cell counts was substantially greater in the maraviroc-treated patients (∼122 cells per mm3 gained), compared with the placebo-treated subjects (69 cells per mm3 gained). Maraviroc was well tolerated. Rates of discontinuation because of adverse events related to study treatment were the same in the placebo and maraviroc groups. Rates of serious adverse events were similar among the treatment groups (∼18%–20%), and rates of laboratory abnormalities were similar among the study groups.
CONCLUSIONS. Maraviroc was well tolerated, and adverse events were no greater than in the placebo group. Maraviroc treatment resulted in greater suppression of HIV, greater increases in CD4+ cell counts, and a greater proportion of individuals who achieved HIV RNA levels of <50 copies per mL.
REVIEWER COMMENTS. This study and its companion article (Fätkenheuer G, Nelson M, Lazzarin A, et al. N Engl J Med. 2008;359:1442–1455) demonstrated that maraviroc is an effective antiretroviral agent. It achieved remarkable success in a very heavily pretreated population. Of particular importance was the need for at least 1 and preferably 2 effective agents in the optimized background regimen to maximize the effect of maraviroc. In addition, in the secondary analysis of the results, preexisting CXCR4-using HIV essentially eliminated any benefit of maraviroc. The development of CXCR4-using HIV after primary infection with CCR5-using virus is a matter of time and chance. Approximately 50% of heavily pretreated, long-term HIV-infected adults have CXCR4-using virus and thus would be completely resistant to maraviroc therapy. Currently, maraviroc is approved for patients who are known to be resistant to multiple other drugs. Perhaps maraviroc and similar chemokine receptor blockers would best be used before the likely development of CXCR4-using virus. Studies are underway to evaluate the use of this novel agent in patients naive to antiretroviral therapy.
- Copyright © 2009 by the American Academy of Pediatrics