AIDS researchers explore new drug options.

Abstract

SAN FRANCISCO—Spurred by such problems as the emergence of drug-resistant strains of HIV and adverse effects of current drug regimens, AIDS researchers are actively seeking new agents that use a novel strategy to foil the virus: blocking HIV’s entry into target cells. A number of groups are focusing their efforts on a promising group of compounds called “entry inhibitors,” according to new findings presented here at the Seventh Annual Conference on Retroviruses and Opportunistic Infections. Because such agents target a different step in HIV’s life cycle than current drugs, researchers hope they will have a useful role in “salvage regimens” for patients who are unable to benefit from established treatments because of drug resistance or toxicity. The entry inhibitor farthest along in the drug development pipeline, T-20, has one significant disadvantage: it must be given by injection. But results of early studies of the agent’s potency will undoubtedly encourage drug developers to work toward developing similar oral compounds. Before HIV can invade CD4 + T cells, it must attach to one of two chemokine receptors, CCR5 or CXCR4, on the cell surface and then fuse with the cell membrane. Scientists reasoned that if they could develop agents that prevented HIV from binding to these receptors or fusing with the cell membrane, infection could be short-circuited. A portion of the HIV envelope protein called gp41 is primarily responsible for fusion of HIV with the cell membrane. Researchers reasoned that if they could synthesize an agent that mimics gp41 and administer it to patients in sufficiently high concentrations, it could block HIV from attacking uninfected target cells. A phase 2 open-label trial of T-20, a synthetic peptide that has the same molecular structure as a portion of gp41, is under way in 47 HIV-positive adults who had been heavily treated with and were no longer responding well to conventional antiretroviral drugs. Patients who had taken T-20 for at least 32 weeks experienced a significant and sustained drop in viral load (exceeding a 1.0 log10 below baseline levels), while CD4 + cell levels had increased and continued to rise. Although the researchers thought that compliance might be hindered by the need to inject T-20 twice daily, a check of blood drug levels in trial participants suggested “a very high degree of compliance,” noted Samuel Hopkins, PhD, of Trimeris Inc, a Durham, NC–based company that is developing T-20 in partnership with F. Hoffmann–La Roche Ltd. “The data suggest that T-20 in combination treatment may be able to provide a durable immunologic and virologic benefit.” Because fusion inhibitors work outside the host cells, they may be less toxic than conventional HIV medications, said Hopkins. Preliminary studies have found that T-20’s primary adverse effect is inflammation at the injection site, although it is unclear what adverse effects might occur with long-term use. Trimeris scientists are also testing T-20 (in combination with other antiretroviral drugs) in patients with less advanced disease and are gearing up for a worldwide phase 3 clinical trial by mid year. A clinical trial in which an experimental fusion inhibitor called T-1249 is being tested in 60 to 70 patients is also under way. Other investigators reported early studies of entry inhibitors that target the CCR5 or CXCR4 chemokine receptors on human cells. Erik De Clercq, MD, PhD, of the Rega Institute for Medical Research, Leuven, Belgium, described work on compounds called bicyclams, which interfere with HIV’s binding to the CXCR4 receptor. A prototype bicyclam, AMD3100, given by injection, was well tolerated in safety studies in healthy volunteers, and efficacy trials in patients with HIV infection are under way, said De Clercq. An in vitro study, also presented at the conference, suggests a strong synergy between T-20 and AMD3100 in controlling infection; whether this synergistic effect would translate into clinical benefits for patients remains to be determined. Researchers from Schering-Plough Research Institute, Kenilworth, NJ, described in vitro and animal studies involving a a small molecule called SCH-C that targets the CCR5 chemokine receptor and may permit oral administration. Animal data suggest that the compound is a potent inhibitor of HIV activity. The company hopes to begin human trials later this year. It’s exciting that new classes of drugs are being developed based on HIV-1 entry inhibition, although challenges remain, said Robert T. Schooley, MD, of the University of Colorado Health Sciences Center in Denver. Nevertheless, he added, “the major excitement is that it’s been shown conclusively that [this approach] works.” h MEDICAL NEWS & PERSPECTIVES