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Among the more sobering news presented at the 8th Conference on Retroviruses and Opportunistic Infections, held February 2001 in Chicago, was the evidence that HIV patients are having numerous side effects from antiretroviral medications.
Hyperlipidemia, fat redistribution, bone disease, metabolic problems, and the threat of heart disease are among the more prominent concerns of clinicians and researchers working in the field of HIV disease. These adverse effects, coupled with increasing evidence of drug-resistant virus, have brought attention to new classes of drugs that could fight HIV on different battlefields and therefore avoid the risk of the same types of drug resistance or side effects.
"We particularly need new drugs that will treat resistant virus," says Charles F. Farthing, MD, medical director of AIDS Healthcare Foundation (AHF) Healthcare Center in Los Angeles. Farthing says the new class of drugs called the entry inhibitors could be one solution to the problem. Three different entry inhibitor classes are being studied: fusion inhibitors, attachment inhibitors, and coreceptor antagonists.
HIV clinicians need new drugs because while protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) are potent, there is increasing concern about toxicity, says John Moore, PhD, professor of microbiology and immunology at Weill Medical College of Cornell University in New York.
"That’s why the treatment guidelines are being changed," Moore says, referring to an announcement made at the retroviruses conference. "The reason for the change is because the PIs and RTIs accumulate toxicities, so people who have to take them have to minimize the amount of drugs they have to take. This highlights the need for new drugs with hopefully negligible or limited toxicity.
"The entry inhibitors have a completely different mechanism of action, which is one reason why this area of research has become so attractive," Moore notes, who has been researching fusion inhibitor compounds in recent years.
Researchers presented a variety of data from studies of entry inhibitors at the recent retrovirus conference. A number of studies assessed the regulation of chemokine receptors CCR5 and CXCR4, while others showed evidence that a T-20 fusion inhibitor could be an effective addition to antiretroviral treatment. (See story about conference abstracts, "Fusion inhibitors intercept virus at cell entry point," in this issue.)
"The whole idea behind this newest area of anti-HIV drug development is to look at blocking virus entry," says Gregory Reyes, MD, PhD, vice president of biological research, infectious diseases, and oncology at Schering-Plough Research Institute in Kenilworth, NJ. Reyes, whose company is developing co-receptor antagonist compounds that target CCR5, spoke at the conference about the development of CCR5 antagonists as a new class of anti-HIV medications.
"The current set of inhibitors for HIV are directed to viral product, while the newer set of compounds targeting CCR5 would actually block the virus from attaching to the cell and entering the cell," Reyes explains. "What is critical for the virus to enter the cell is to first bind to CD4 and then utilize the co-receptors, and the two principal co-receptors are CCR5 and CXCR4."
HIV uses the CCR5 co-receptor early in the course of HIV infection. About 40% of the time, after the virus evolves and mutates and the disease progresses, the virus gains entry to the CXCR4 co-receptor, Reyes says. "So the idea is if you can block virus entry with CCR5 and CXCR4 antagonists, then you are indeed blocking the viral life cycle," he says.
As an interesting side note, CCR5 is the major co-receptor for transmitted viruses, and the absence of CCR5 in humans has no negative effect on their health, Moore says. "About 1% of Caucasians naturally lack CCR5, and that doesn’t impact their health," Moore notes. "But that is strongly protective against HIV transmission, so if you have a complete absence of CCR5, it is strongly protective against getting HIV in the first place."
Schering-Plough currently has two co-receptor antagonist compounds under study. One called SCH-C is a CCR5 antagonist that has undergone Phase I clinical trials but has been put on clinical hold because of potential cardiac problems at very high doses, Reyes says. "I think that some of the data I presented indicated that we are getting tremendous exposures in individuals and could easily achieve viral inhibitory levels at much lower doses than the doses where we saw the problem," Reyes says. "So now we’re taking a close look at the data, and we’re in the process of investigating preclinical models."
The second compound is Schering-Plough’s SCH-D, which is a second-generation compound that has demonstrated very high potency in preclinical data. Research into this compound is still in its early stages, he says.
Schering-Plough’s two compounds would have the additional advantage of being taken orally, if they are successful in future clinical studies and make it to market. Reyes points out that such fusion inhibitors could be used in combination with current antiretroviral treatment, potentially boosting potency without increasing resistance to the current classes of antiretrovirals.
SCH-C has shown some resistance to the compound, but the other CCR5 antagonists appear to be active to this resistance, so there is no data suggesting a broad cross-resistance to the CCR5 antagonists, Reyes says.
A prototypic fusion inhibitor called T-20, developed by Trimeris Inc. of Durham, NC, is among the first of its kind to be tested in Phase II and Phase III clinical trials. T-20 has demonstrated some efficacy, Moore says.
"The problem with T-20 is it is an injectable and can’t be taken orally, so it’s not easy to take," Moore says. "This is a limiting factor, an inconvenience, but the drug still is useful to have, and T-20 does give you proof of concept, saying that a fusion inhibitor can have an effect in vivo."
Investigators also are looking at the use of fusion inhibitors as a preventive strategy, such as using them in microbicides as a prophylactic measure, Moore says. "In absence of a vaccine, and the world does not have an effective vaccine, how do we prevent sexual transmission of HIV?" Moore asks. "One possible way of doing that is to use this kind of compound to apply topically as a vaginal or rectal cream and see if it prevents virus from taking hold."
Moore predicts such studies are likely to take place with various fusion inhibitors, particularly because federal grant money is being directed to this area of research. "This is a credible area of research," he adds. However, most entry inhibitor research is still years away from producing marketable products; therefore, other short-term solutions will need to be found to prevent patients from failing current therapy.
A solution might be advanced-generation antiretrovirals, such as the protease inhibitor lopinavir/ ritonavir (Kaletra), which has not encountered resistance in PI-naive patients according to 48-week data. (See "Kaletra is potent addition to antiretroviral therapy," in this issue.)
"Kaletra is a well-studied drug, and I think it’s fair to say it’s more potent than anything else we have at the present time, and certainly within the protease inhibitor class, it’s definitely the most tolerable," Farthing says.