NewYork-Presbyterian Hospital/Weill Cornell Medical Center's Dr. Roy Gulick Is Lead Investigator of Phase 3 Multicenter Trial; Results in Oct. 2 New England Journal of Medicine
New Class of HIV Medication Takes Upper Hand Against Drug Resistance
Oct 2, 2008
As many as one quarter of HIV patients have drug resistance, limiting their treatment options and raising their risk for AIDS and death. Now, maraviroc, the first of a new class of HIV drugs called CCR5 receptor antagonists, has been shown to be effective over 48 weeks for drug-resistant patients with R5 HIV-1, a variation of the virus found in more than half of HIV-infected patients.
Results of the two Phase 3 multicenter MOTIVATE (Maraviroc Plus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients) studies led by NewYork-Presbyterian Hospital/Weill Cornell Medical Center's Dr. Roy Gulick and published in the October 2 issue of the New England Journal of Medicine (NEJM) find that the drug, taken with an optimized standard HIV drug regimen, resulted in significantly greater suppression of the virus at 48 weeks, with concurrent increases in immune system T-cell counts, when compared with placebo. Rates of side effects were not different between the maraviroc and placebo groups.
Preliminary results of these studies led to FDA approval of maraviroc in August 2007.
Because it is from a new class of HIV medications known as HIV entry inhibitors, people living with HIV generally will not have resistance to maraviroc because they have not been exposed to any drugs from the class previously. Unlike earlier HIV drugs that target the virus, maraviroc acts on the human T-cell, binding to it in such a way that prevents HIV from binding and subsequently infecting the T-cell.
"It is now possible to expect that a majority of treatment-experienced patients who experience failure on their current HIV drugs will regain control of their HIV infection with maraviroc combined with other newer antiretroviral drugs. This is an important step forward," says study principal investigator Dr. Roy Gulick, who is professor of medicine and director of the Cornell HIV Clinical Trials Unit of the Division of International Medicine and Infectious Diseases at Weill Cornell Medical College, and a practicing physician at NewYork-Presbyterian Hospital in New York City. "Suppressing virus levels and increasing immune system T-cells with HIV treatment regimens helps HIV-infected people live longer, healthier lives."
The double-blind study followed 1,049 of patients with advanced HIV and resistance to three antiretroviral drug classes. Patients were randomized to receive maraviroc once-daily, twice-daily or placebo. Safety and efficacy were assessed at 48 weeks. The MOTIVATE studies comprised two identical arms: MOTIVATE1 was conducted in Canada and the U.S., while MOTIVATE2 was conducted in Australia, Europe and the U.S.
More patients receiving maraviroc once- or twice-daily versus placebo achieved HIV-1 RNA <50 copies/mL (43-46% vs. 17%). CD4 counts increased more with maraviroc once- or twice-daily versus placebo (+116-124 vs. +61 cells/µL). Frequencies of side effects and toxicities were similar across groups.
A subgroup analyses of the MOTIVATE trials is also published in the October 2 edition of NEJM. "Findings from the subgroup analyses show that maraviroc plus standard antiretroviral regimen provides consistent clinical benefit over placebo plus optimized background therapy for all subgroups analyzed," said Dr. Gerd Fätkenheuer, lead-author of the subgroup analyses and professor of medicine, Universitätsklinik Köln, Köln, Germany. "Results highlight that maraviroc provides a valuable additional treatment option for a wide spectrum of treatment-experienced patients with R5 HIV-virus infection."
Currently there are 25 FDA-approved HIV medications in six classes, including HIV entry inhibitors like maraviroc, used in various combinations to treat HIV and AIDS. In cases of drug resistance, medicines lose their ability to fight HIV. Some drugs become less effective while others can become completely ineffective. As viruses reproduce, they make copy after copy of themselves, growing in number with each replication. Sometimes, small errors in one virus will be passed on to the next viral copy. Over time, viruses that contain these small errors become larger in number. These small changes in the virus's genetic make-up are called mutations. It's these mutations that cause resistance to HIV medications. Often, resistance to one medication means resistance to an entire class of medications.
Study co-authors include Dr. Jacob Lalezari of Quest Clinical Research and Mount Zion Hospital of the University of California, San Francisco; Drs. Michael W. Dunne, James Goodrich and Howard Mayer of Pfizer Global Research and Development, New London, Conn.; Dr. Nathan Clumeck of C.H.U. St-Pierre, Brussels, Belgium; Dr. Edwin DeJesus of Orlando Immunology Center, Orlando, Fla.; Dr. Andrzej Horban of Wojewodzki Szpital Zakazny, Warszawa, Poland; Dr. Jeffrey Nadler of the University of South Florida College of Medicine, Tampa, Florida; Dr. Bonaventura Clotet of Fundació "irsicaixa" and Hospital Universitari "Germans Trias i Pujol," Badalona, Spain; Dr. Anders Karlsson of Venhälsan, Karolinska University Hospital, Stockholm, Sweden; Dr. Michael Wohlfeiler of Wohlfeiler, Piperato & Associates, North Miami Beach, Fla.; Dr. John B. Montana of New York; and Drs. Steve Felstead, Mary McHale Caroline Ridgway, Elna van der Ryst and Mr. John Sullivan of Pfizer Global Research and Development, Sandwich, U.K.
The MOTIVATE studies were supported by Pfizer. Dr. Gulick has received consultancy fees or grant support from Pfizer and other companies whose business interests are relevant to this study, including Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Monogram, Pfizer, Schering-Plough, Tibotec, Virco and ViroStatics.
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NewYork-Presbyterian Hospital/Weill Cornell Medical Center
NewYork-Presbyterian Hospital/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital NewYork-Presbyterian and Weill Cornell Medical College, the medical school of Cornell University. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, education, research and community service. Weill Cornell physician-scientists have been responsible for many medical advances — from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and, most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. NewYork-Presbyterian, which is ranked sixth on the U.S.News & World Report list of top hospitals, also comprises NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/Westchester Division and NewYork-Presbyterian Hospital/The Allen Pavilion. Weill Cornell Medical College is the first U.S. medical college to offer a medical degree overseas and maintains a strong global presence in Austria, Brazil, Haiti, Tanzania, Turkey and Qatar. For more information, visit www.nyp.org and www.med.cornell.edu.