New Protease Inhibitors May Fight HIV Resistance

A "new generation" of protease inhibitors shows promise in fighting HIV strains that have developed resistance to "standard" drugs currently available, researchers announced yesterday at the 8th Conference on Retroviruses and Opportunistic Infections. The drugs may offer a two-fold benefit: They "seem able" to attack resistant HIV strains, and one prototype of the drug, TMC-126, may also be able to "suppress the development of new varieties of resistant virus," the Philadelphia Inquirer reports. John Erickson of Tibotec Group NV, the Belgian company that is developing the new class of protease inhibitors, describes the combination of these two features as "resistance-repellence." The drugs "look promising" in test tube studies, blocking viral replication and working across a "broad spectrum" of HIV strains that are resistant to standard therapies, but researchers have just begun human testing of one prototype, TMC-120. Two other prototypes, TMC-125 and TMC-126, are still undergoing preclinical testing. Erickson said if the drugs pass clinical testing, they could be used to help AIDS patients "who have failed other treatments as well as be front-line therapy for those with newly diagnosed infections" (Philadelphia Inquirer, 2/6).

Protease Inhibitors and Viral Resistance
HIV's ability to mutate into resistant strains has been one of the biggest roadblocks in HIV/AIDS treatment. "There is a real and growing need for drugs to fight resistance," David Ho, director of the Aaron Diamond AIDS Research Center in New York, said. "Nobody really knows the exact size of the problem, but it's likely affecting about one-third" of those taking drug combinations, Ho added. The Wall Street Journal reports that there are two main causes of resistance: people who skip doses of HIV therapy, which allows the virus to "emerge in mutated forms" and "eventually overwhelm" the drugs; and mutation that occurs "simply by chance" when even just a "tiny bit" of virus is left in the body during therapy. The advent of protease inhibitors in 1996, in combination with AZT and other medicines, originally seemed to eradicate the resistance problem resulting from HIV drugs that "only partially" blocked viral replication. Protease inhibitors work by "binding snugly inside a tiny pocket" within the HIV protease enzyme, an enzyme "critical" to HIV replication. But some HIV strains have developed genetic mutations that change the shape of this enzyme pocket "in a way that the drug no longer can fit inside of it." However, Tibotec's new class of protease inhibitors is "flexible" in its apparent ability to "shift as needed to accommodate the variable pocket shapes," and therefore is effective against a number of mutant HIV strains (Waldholz, Wall Street Journal, 2/6). Ho said of Tibotec's drugs, "We have for the first time a very, very powerful protease inhibitor that could suppress resistant virus. That's pretty impressive" (Philadelphia Inquirer, 2/6). "It's really exciting," Douglas Richman, a researcher at the University of California-San Diego and a conference organizer, concurred, adding, "But one should never underestimate the virus's potential for malice and mischief." Scott Hammer, an AIDS-research physician at Columbia University and a Tibotec consultant, said, "The preliminary information I've seen is very encouraging," but he warned that the drugs are in "early stages" of testing and "may yet fail due to toxicities not yet seen" (Brown, Washington Post, 2/6).

33% of Patients Develop Resistance
In other HIV resistance news, Agouron Pharmaceuticals, a Pfizer company, yesterday released a study that showed that 33% of patients experience HIV resistance after initiation of antiretroviral therapy. The telephone-administered survey was conducted among 300 physicians who had written at least 22 prescriptions for HIV medications in the past month and treat an average of 120 patients. In addition, the survey found that 35% of patients receive a "single protease inhibitor combination," 18% receive a single non-nucleoside reverse transcriptase inhibitor-based combination and 12% receive a triple nucleoside analogue combination. Among physicians who administered single protease inhibitor combinations as "first-line therapy," 30% chose the protease inhibitor based on "drug tolerability," while 21% cited "resistance profile" and 26% indicated drug "efficacy" when choosing a particular protease drug. When choosing a single protease inhibitor, 63% were found to prescribe nelfinavir, manufactured by Agouron (Agouron release, 2/5).

Once-Daily Protease Inhibitor
Another new protease inhibitor presented yesterday at the conference was "safe, tolerable and effective" when "holding off" HIV in patients with only one dose a day (University of Southern California release, 2/5). Kathleen Squires of the University of Southern California presented a 48-week study of a new protease inhibitor developed by Bristol-Myers Squibb called BMS-232632, in which the new drug was compared to the "popular" protease inhibitor nelfinavir in combination with other antiretrovirals. The study showed that about 65% of study participants receiving the BMS drug and "a similar fraction" of those on the nelfinavir combination had HIV viral load counts fall to "undetectable levels." But patients on the BMS drug had "only a slight rise of cholesterol ... and no rise in triglycerides, another bloodstream fat." A rise in bloodstream fats is a typical side effect associated with all current protease inhibitors, and a problem experienced by about 70% of patients taking protease inhibitors (Washington Post, 2/6). However, Squires noted, "It remains to be seen whether BMS-232632 has the potential to avoid other long-term complications such as lipodystrophy," but stressed that the new drug "offers patients once-daily dosing, and the additional benefit of low pill burden" (University of Southern California release, 2/5).