Antiretrovirals: The Next Generation

HIV specialist Tony Mills has not admitted any of his patients to the hospital for HIV-related opportunistic infections for nearly four years. Instead, every hospital stay has been linked with cardiac problems arising from HIV disease or, as more commonly believed, the antiretroviral drugs used to treat it. 'I tell my patients that the two chief concerns I have'because I'm convinced I'm going to be taking care of them for the next 40 years'are drug resistance and long-term toxicities to the medications,' says Mills, whose practice is based in Los Angeles. 'It's very important that we start to target specific therapies that have low side effects and low toxicity profiles.' Mills's perspective is not unusual. HIV experts are increasingly concerned about the adverse long-term effects of highly active antiretroviral therapy, particularly the apparent link between anti-HIV drugs and elevated cholesterol and triglyceride levels, which can boost a person's risk for heart attacks, strokes, and other cardiovascular ailments. New studies presented this year have only heightened those fears. One European study has found that the risk of heart attack increases by 26% for each year an adult takes anti-HIV drugs. Another has suggested that protease inhibitors double an HIV-positive person's cardiac risks, an increase greater than that caused by smoking. Researchers at the University of California, San Francisco, have reported that HIV patients taking antiretroviral drugs for an average of four years had more arterial buildup than even elderly men who have had a heart attack. While cardiac risks are a chief worry for HIV caregivers, anti-HIV drugs also have been linked with numerous metabolic complications: lipoatrophy, insulin resistance, diabetes, lactic acidosis, and visceral fat accumulation. 'These long-term toxicities really caught us by surprise,' says Karen Tashima, MD, director of HIV clinical trials at Miriam Hospital in Providence, R.I. 'We're studying those kinds of toxicities and are looking for the best treatment for them. Ideally, we'd like to not use medications that cause them.' Taking Note Pharmaceutical companies are hearing that message loud and clear, says Michael Gottlieb, MD, who in 1981 was one of the first physicians to report on AIDS-related Pneumocystis pneumonia among his patients. 'If a company is developing a nucleoside analog, it is likely one of the early studies will be to investigate if it causes mitochondrial toxicity,' he says. 'If it does, it might not be slated for development. If it doesn't, the company would likely slate it for fast-track development.' Alvan Fisher, MD, director of medical affairs for pharmaceutical company Gilead Sciences'the maker of Viread and the once-daily nucleoside reverse transcriptase inhibitor Emtriva'says his firm focuses only on potential drugs that could offer distinct advantages over existing ones. This includes medications that are active against HIV strains resistant to existing drugs, that are more potent than available antiretrovirals, that do not cause the adverse side effects linked with existing medications, or that are easier to take. 'Simplicity is the key,' Fisher explains. 'If a regimen is more complex, people are more likely to be nonadherent,' which can lead to drug-resistant virus. 'The first step in prevention of resistance is making simpler regimens so that people will adhere better.' But drug resistance already exists, and the problem is worsening, says Christos Petropoulos, vice president of research and development at ViroLogic, which specializes in drug resistance testing. A study conducted by researchers in San Diego in conjunction with ViroLogic found that about half of all HIV-positive people on antiretroviral therapy are infected with virus with at least one mutation conveying resistance; the figure climbs to more than 70% for those with detectable viral loads. Wasting No Time To provide treatment options for people with dwindling medication choices, drug companies are fast-tracking promising candidates that show effectiveness in combating drug-resistant virus. One such medication to reach the market is the Bristol-Myers Squibb protease inhibitor Reyataz (atazanavir). While offering the advantages of being taken just once a day and not boosting lipid levels, Reyataz also has an unusual drug resistance profile that separates it from other protease drugs. An experimental drug generating considerable buzz for its ability to inhibit drug-resistant virus is Boehringer Ingelheim's second-generation protease inhibitor tipranavir. While other protease drugs are peptide-based medications, tipranavir has a unique, nonpeptidic structure that in theory allows it to remain effective against protease inhibitor'resistant virus and possibly even withstand HIV's attempts to mutate resistance to it. Data from a subset study of 216 highly treatment-experienced patients supports that theory, says Scott McCallister, senior director of virology at Boehringer Ingelheim. All of the patients who were resistant to every available protease inhibitor responded to tipranavir. Many other experimental compounds are being designed to fight drug-resistant strains of HIV as well. 'The current pipeline in HIV drug development is the fullest it has been since 1995'96 and more robust than ever in terms of novel approaches to HIV treatment,' says Jill Leonard, project director of Cincinnati's Kendle International, which helps manage HIV drug trials for pharmaceutical companies. 'It is indeed hopeful to see many of those involved in development research rise to the challenge, and it is not a moment too soon.' Proceeding With Some Caution But while each new anti-HIV drug that reaches the market is hailed by AIDS activists and health care providers, there is a widely held false belief that a single new medication can revolutionize HIV treatment, says Judy Currier, MD, associate professor of medicine at the University of California, Los Angeles. Petropoulos adds, 'The least effective thing you can do is to switch to a new drug without adding other new drugs. Any new drug will be destined to fail if it's not combined with other effective drugs.' Because of this, Mills says he is delaying prescribing Fuzeon, the only approved fusion inhibitor, whenever possible. 'A lesson we've learned in HIV medicine is that it's pretty easy to play all your cards and end up with nothing in your hand,' he explains. 'I'm trying to hold my Fuzeon card tight to use it with other new drugs to have optimal benefit.' Fortunately, the pipeline is practically bursting with experimental drugs in several new medication classes. Drugmakers Trimeris and Roche are conducting Phase I and II human trials of a follow-up drug to Fuzeon, T-1249, which appears to be more potent. Other experimental fusion inhibitors aim to inhibit key viral genes, jam one or both of two CD4-cell receptors the virus attaches to, or otherwise inhibit the virus's ability to fuse to the cell. Another new class of drugs is the integrase inhibitor, which targets an untouched step of viral replication in which HIV's genetic material is inserted into normal cellular DNA. Nicholas Bellos, president of Southwest Infectious Disease Associates in Dallas, says integrase inhibitors were studied in the past, but the drugs were riddled with so many toxicity problems that their development was halted. But new candidates that in lab tests appear to be significantly less toxic are now moving through preclinical development. There are also medications being studied called 'zinc finger inhibitors,' which disable a part of HIV that plays a key role in assembling new copies of the virus as it leaves infected cells. Looking Even Further Ahead Perhaps the most encouraging area of drug development is also the most futuristic'the insertion of engineered genetic material into the body's cells to interfere with HIV's RNA, essentially short-circuiting the virus's ability to replicate. Referred to as RNA interference, the process scrambles HIV's messenger RNA to prevent the virus from creating or using key viral or cellular proteins. While current anti-HIV drugs cannot wipe out viral reservoirs that lie dormant in the body because they target only actively replicating virus, RNA interference may alter HIV's genetic code anywhere, possibly shutting it down for good. 'My hope with the RNA inhibitors is that we may be able to cure people,' Mills says. 'We didn't have the slightest hope of doing so even two years ago. But some of this work is so exciting that I have optimism that we may be able to eradicate the virus from the body.' Although most researchers are a bit less optimistic than Mills, all believe that HIV treatment will be radically different just a few years from now, likely drawing on medications that hamper several steps of viral replication, boost immune responses to HIV, and work to disable the virus at its most basic genetic level. 'We can see coming forward once-daily regimens of just two pills a day; that's already on the horizon,' says Fisher. 'In 10 years maybe we'll have just one pill to take a day or even one pill to take per week. I am very optimistic that treatments will be better, easier and less frequent to take, less toxic, and less associated with resistance. I think that's very realistic.'