Written By Adrienne Sussman

BIO + MED

written by ADRIENNE SUSSMAN

New AIDS Drugs Two new classes of medications complete clinical trials at Stanford

Watch out, viruses: the recent FDA approval of two new classes of antiretroviral medications promises to turn the tables in the fight against HIV/AIDS. While several powerful drug treatments have appeared in the last few years, the HIV virus’s capacity for rapid mutation continues to thwart treatment. The slippery virus mutates so quickly that resistant strains appear quickly – sometimes breaking through every combination of drugs that doctors can throw at it. For patients with highly resistant viruses, the new drugs – maraviroc, from Pfizer, Inc., and raltegravir, from Merck & Co. - help overcome this problem by targeting the virus in different stages of its reproduction. In combination with the currently available medications, these new drugs are able to control even the most resistant strains of the virus, helping many more patients live relatively normal lives in the face of the infection. The drugs completed the last stage of clinical testing at Stanford Positive Care Clinic, where they have been creating dramatic results in Bay Area patients with advanced-stage HIV infections.

The Plan of Attack

The two new drugs are a leap forward in the field because they attack the HIV virus in completely new ways. The most important existing drug classes, the protease inhibitors, nucleoside inhibitors, and non-nucleoside inhibitors, target two very specific aspects of the virus life cycle: the reverse transcription process, where the virus copies its RNA

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into DNA, and the cleaving of long chains of polyproteins into new viruses after that transcription is complete. Since their release in the 1990s, these medications have greatly controlled the HIV/AIDS epidemic and the severity of the disease in those infected. After prolonged use of the existing medications, however, some patients develop new, resistant infections, which are no longer suppressed by the drugs they have been using. This is where the new medications step in. Maraviroc is a CCR5 inhibitor, which blocks the AIDS virus from entering the T-cells of the immune system through its usual molecular entrance, a cytokine coreceptor called CCR5. Raltegravir, on the other hand, is an integrase inhibitor, which means that it prevents a newly transcribed strand of viral DNA from joining with the cell’s own DNA and reproducing. These two molecular targets are key points in the virus’s life cycle, and so blocking these processes can powerfully suppress the virus’s spread. More importantly, these are completely new targets, so even the resistant viruses which no longer respond to protease, nucleoside, or non-nucleoside inhibitors might be conquered by an integrase or CCR5 inhibiting drug.

The Lazarus Effect

The evidence for just how effective these new blocking mechanisms can be was demonstrated in the recent clinical trial at Stanford Positive Care Clinic. The clinic is a 14-year-old research and treatment center located on the Veterans Hospital campus which specializes in virology and the study of resistance. Researchers at the clinic have been involved in hundreds of clinical trials and treated thousands of patients.

The director of the clinic, Dr. Andrew Zolopa, was excited by the responses he saw in his patients during the trials. Dr. Zolopa compares the dramatic effects that these new medications can have, to the medical turning point ten years ago when protease inhibitors were first introduced on the market. At that point, Zolopa says, “we saw and heard reports of these Lazarus-like effects, of patients who were near death with end stage AIDS, recovering fully and getting back to work and back to life.” Unfortunately, protease inhibitors weren’t a miracle-cure for all. As Zolopa explains, even the drugs of the 1990s “still left a number of patients who didn’t have a completely suppressive regimen, had too much resistance coming into their new treatment regimes. Those patients have been kind of hanging on for most of this past decade.” The new drugs, however, have been successfully treating these extremely resistant patients, offering relief where the protease inhibitors were not strong enough. As an example of the transforming effect of these medications, Dr. Zolopa tells the story of one of his own patients who recently started treatment with raltegravir. “He had zero T-cells for the last five years, I mean no T-cells,” Zolopa explains, “and then with the new drugs, he’s been able to get viral loads almost fully suppressed, and his T cells are coming back again. So it really is like a second wave of these Lazarus-like recoveries in patients who have been waiting a long, long time to find an effective regimen.” As exciting as the new medications are, they have their limitations. Maraviroc may not be helpful for some advanced stage patients, as the HIV virus tends to evolve to utilize other pathways for entering the cell. This means

Target Resistant Virus

A Treatment, Not a Cure

As culmination to several years of rapid drug development, in the past two years alone researchers have developed two new types of protease inhibitors, as well as a new kind of non-nucleoside inhibitor. The new drugs attack the same aspect of the virus’s reproduction as their predecessors, but are more powerful and have fewer debilitating side-effects. In other developments, pharmaceutical researchers have created a single multi-drug pill that is effective for newly infected patients, simplifying the often complicated drug regimen of most HIV/AIDS patients. In short, things look bright in HIV/AIDS treatment, and most patients are now able to suppress the virus almost fully. Still, while a huge step forward, these new drugs are not a panacea, but rather a useful weapon when combined with the existing arsenal of options. The HIV virus can still develop resistance to these drugs if they are administered alone; the drugs must be used as part of a multi-medication regimen. When multiple drugs are taken together, the infection becomes so weak that it is much more difficult for the virus to develop resistance. The average HIV patient needs a drug cocktail of 3 or more active medications to fully suppress the virus – a regimen that can be complicated and taxing for the patient.

The newly available drugs will not simplify the course of therapy, nor will they guarantee against the appearance of new resistant virus strains. However, Dr. Zolopa predicts that resistance, while it may occur, will reach an asymptote with the new drugs. “There are fewer and fewer patients who are breaking through their third line and fourth line and fifth line regimens. With each new wave of development, we are able to fully suppress and successfully treat another portion of the patients,” he explains. Exciting as these new developments are, Zolopa cautions that the HIV/AIDS epidemic is far from controlled. The number of infections is growing, both in the United States and around the world, and as few as 10% of those infected are receiving treatment. In addition to the simple problem of inadequate access to therapy, Dr. Zolopa describes a balance between the benefits and risks that new medications bring. While new drugs are extremely valuable, they also bring the slight risk of creating ever more resistant versions of the virus. Moreover, the availability of such powerful treatments in this country has perhaps led to a relapse of risky behaviors, allowing the infection to spread to a greater number of people. Despite the continued need for prevention measures, thanks to these new drugs, the future looks bright for those in treatment.

After prolonged use of the existing medications, however, some patients develop new, resistant infections, which are no longer suppressed by the drugs they have been using. This is where the new medications step in.

ADRIENNE SUSSMAN graduated last year with a degree in biology and will begin a PhD program at the University of Washington in the fall.

To Learn More

For more information on raltegravir, maraviroc, and other AIDS treatmets and research, visit www.aidsinfo.nih.gov. For information on the AIDS virus and epidemic, visit www.cdc.gov/HIV.

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that for patients who have been infected for a long time – the patients who are most desperate for new drugs - CCR5 inhibitors like maraviroc may not be effective. Raltegravir, on the other hand, does help patients at every stage of infection, as integrase, its target, directs one of the vital steps in the virus lifecycle.