New weapons on the way in battle against mutating HIV

Expect more powerful meds in the next five years

Research clearly shows that HIV is a resilient and crafty virus that can rapidly adapt to its surroundings and begin to rebound against some of the most potent antiretroviral medications on the market.

While it has taken decades for some viruses to develop drug-resistant strains, HIV mutates so rapidly that its drug-resistant strains have taken mere years to grow in strength. Although this may cause some clinicians and HIV patients to despair of ever finding a cure for the disease, it has served as a hearty challenge to pharmaceutical companies that are racing to bring the newest, most potent HIV drugs to market.

The next generation of drugs will have been tested for the ability to defeat drug-resistant viral strains, including viruses that have found ways to get around the major protease inhibitors.

"There definitely are several promising drugs in development that have been targeted against resistant viruses," says Richard D’Aquila, MD, associate professor of medicine at the Harvard Medical School and Massachusetts General Hospital in Charlestown, MA.

"Until now, HIV drug resistance has been seen as a more limited problem, and therefore there’s a more limited market for new drugs," D’Aquila notes. "Now we’re beginning to realize these viruses are increasingly going to be a problem, and many companies are focusing more attention on developing drugs specifically against resistant viruses."

Pharmaceutical companies are taking note. For instance, companies like Glaxo Wellcome Inc. of Research Triangle Park, NC, are devoting a great deal of research and resources toward developing drugs that are effective against drug-resistant HIV strains.

"We were studying resistance to AZT from practically the time when it went out on the market, and maybe even before that," says Eric Furfine, PhD, senior research investigator of Glaxo Wellcome.

"If you look at HIV drugs’ failure rate over two years’ time, roughly 50% of patients taking a triple-drug regimen, even naive patients, fail therapy for whatever reason," Furfine says. "Usually, it’s just one of the three drugs that fails, but it’s enough to permit the virus to rebound."

Besides the fact that new drugs will be needed to keep HIV patients healthy and living longer, new technologies also are pushing drug resistance research forward. Now there are better methods for detecting resistant virus strains. Both genotyping and phenotyping may soon become standard tests for clinicians who want to make sure they select the most effective drug combination for HIV patients. AIDS researchers have discovered that nearly 28% of people who are newly infected with HIV may have become infected with a virus that is resistant to one or more antiretroviral drugs. (See AIDS Alert, December 1999, p. 133.)

These are among the most exciting times with regards to HIV research, partly because of the success of protease inhibitors and the current wide array of drugs available for treating HIV, says Daniel Kuritzkes, MD, associate professor of medicine and microbiology at the Division of Infectious Disease at the University of Colorado Health Sciences Center in Denver.

"When we saw the first wave of patients failing on HIV drugs, there was a lot of concern because we had nothing else available," Kuritzkes says. "But now there are 20 drugs currently in development from different classes, including several novel classes of antivirals."

New drugs target resistant strains

And most of these new drugs show potential for having activity against some of the drug-resistant HIV strains, he adds.

In fact, most drugs under development now are being designed to work against drug-resistant virus. These include new nucleoside reverse transcriptase inhibitors, protease inhibitors, and non-nucleoside reverse transcriptase inhibitors.

"In addition, there are a whole series of virus entry or virus fusion inhibitors that are in earlier stages of development but are showing prom ise," Kuritzkes says. "Then there are the integrase inhibitors that are finally making their way to early clinical trials. So there’s a lot of reason to be optimistic that we’re seeing considerable effort at stopping resistant mutations."

While researchers stage a stealth battle to undermine drug-resistant virus and HIV’s mutation rate, clinicians can help from the war’s front lines. Their challenge is to use new and existing drugs correctly by combining them for greater potency, rather than simply adding them on top of failing regimens, Kuritzkes says.

"We’ll always be in a race with the virus, much as we are with standard antibiotics," he notes. "But this is a much faster-paced race because of the speed with which HIV replicates and generates mutation."

HIV is probably the most complex chemo therapeutic challenge in medicine, says Bruce McCreedy, PhD, vice president for clinical vir ology and diagnostics at Triangle Pharma ceu ti cals in Durham, NC.

"We learned very early on, in the late 1950s, that the way to treat TB is you hit it early with good potent combinations up front, and then you can get rid of the organism," McCreedy says. "Whereas with HIV, even a solid good potent combination is not able to eradicate the virus."

Medications can suppress, not cure

Medications will only suppress the virus because it hides in places in the body that the drugs have trouble reaching.

This means the best treatment solution is to suppress the virus for as long as possible through use of very potent medications. These drugs’ potency will fade with time in any particular patient, but pharmaceutical companies are trying hard to stay ahead of resistant strains by creating new and different medications. (See story on new and existing drugs, p. 10.)

"I think we all would agree in the field that we need some drugs that work against resistant viruses, as opposed to some drugs that look great in naive patients," McCreedy says.

Clinicians can stay ahead of this problem through careful monitoring of the patient’s viral load and altering drug combinations when a particular medication begins to fail.

With increasing numbers of HIV antiretrovirals to choose from and more than 1,800 combination possibilities, clinicians may find it difficult to select the most effective combination that can be tolerated by patients, McCreedy says.

"The second challenge is: How do you plan therapies for patients who begin to fail on a first regimen or don’t tolerate it?" he adds. "So the challenge is not only to find molecules that are active against resistant viruses; the challenge is how to put a combination of drugs together that may allow options after the first failure."

When HIV drugs are used correctly, they are potent and will suppress the virus. This means patients need to be closely monitored and then switched to a new fully active set of drugs as soon as the first combination begins to fail, D’Aquila says.

Physicians who follow this pattern will have patients who do much better on antiretrovirals, and they’ll avoid major problems with resistance, he adds.

Soon, clinicians routinely will use resistance tests to determine which drugs are failing in a combination therapy. Previously, if a patient was on a three-drug regimen and the clinician saw viral replication return, then he or she would assume that none of the drugs had any activity against HIV, says Robert Schooley, MD, head of the infectious disease division of the University of Colorado in Denver.

"We now know that if you follow a patient’s viral load closely, the drugs fail sequentially, and that it might well be the case that in a three-drug regimen you have resistance only to one of the drugs," Schooley says. "And that means the other two drugs can still be used in the future in treating that patient."

Being able to salvage drugs will be very important as patients live longer with the disease, he adds.

Clinicians also play an important role in educating patients about HIV prevention and medication adherence.

Researchers say most drug failures occur because patients did not adhere to their combination therapies. When the virus has even short-term breaks from antiretroviral drugs, it can begin to replicate and mutate into strains that are no longer affected by those drugs.

"When you have previously HIV drug-naive patients come into treatment and receive a drug regimen they can tolerate, then I would say 80% to 90% of these people are able to have their virus suppressed," Kuritzkes says. "The failures are in general caused by problems with medications where people have difficulty adhering to their medication regimen."