New research data show more drug resistance but also more care options

While better treatments available, more can be done

While clinicians and researchers are seeing increasing numbers of HIV patients with multidrug-resistant virus, there are indications that some existing drug combinations continue to be potent against resistant virus.

"As in much of HIV news, there is reason for pessimism as well as optimism," explains Rodger MacArthur, MD, an associate professor of medicine in the division of infectious diseases and director of HIV/AIDS clinical research at Wayne State University in Detroit and Detroit Medical Center.

"We’re seeing more and more patients with multidrug-resistant virus — both in patients who have been extensively treated and have not adhered to their regimens particularly well, as well as in patients who were following the best medical advice," he says.

"Resistance is common in clinical care, but that needs to be tempered by the recognition that a lot of patients in clinical care in the United States have extensive therapy experience," says Sonia Napravnik, PhD, epidemiologist with the division of infectious diseases at the University of North Carolina in Chapel Hill.

"I think as the resistance information is being used more often in research settings and clinical settings, we have a better sense of how to manage the development of resistance, how to sequence drugs to preserve more options," she notes.

Clinicians should be prepared to see increasing drug resistance, explains Ladislau Kovari, PhD, an associate professor of biochemistry and molecular biology at Wayne State University.

"Unfortunately, as we have more and more antiretroviral drugs, this problem of treatment failure and drug resistance is going to increase," he explains.

"In the past, pharmaceutical companies were less interested in coming up with treatment for the drug-resistant virus, but I think we’re getting close to a tipping point," Kovari adds. "And other scientists and myself and our collaborators are trying to anticipate the needs and solve this important problem."

What’s the good news?

The good news regarding protease inhibitors and resistance is new research has shown that tipranavir plus ritonavir seem to work well against resistant virus, MacArthur says.

"At one year [with treatment to tipranavir plus ritonavir], one-third of patients with resistance to protease inhibitors were able to get to undetectable virus in their blood," he adds.

"We also know a lot more now about how to avoid or treat resistant virus," MacArthur says. "We know in terms of avoiding it that we must emphasize adherence to patients, and we have to do whatever we can in the medical profession to come up with regimens that are easier to take and that are more forgiving."

Unfortunately, it’s not easy to come up with a pill that is both easier to tolerate and more potent, he notes. For example, the non-nucleoside reverse transcriptase inhibitor (NNRTI) class has a low pill burden, a long half-life, and an easy-to-take formulation, MacArthur says.

"But it’s very unforgiving in terms of missed dosage, so major resistance mutations develop to this class very quickly; and once it occurs, it can extend to any drug in that class," he says. "We must protect drug classes, if we can, that are somewhat fragile."

The key is for clinicians to continually try to balance potency, tolerability, and adherence, MacArthur points out.

"We know from many studies that patients show certain consistent factors with poor adherence, including active use of street drugs, homelessness, psychiatric illness," he says. "For those individuals, we probably would not want to risk using or losing a class by using NNRTIs up front."

Although NNRTIs are potent and easy drugs to take, they won’t be of much benefit to patients who do not understand that they must be taken 100% of the time, MacArthur adds.

Data now show that with most drug regimens, the adherence rate that poses the greatest risk for the development of drug resistance is 80%, he says.

"Most people would say that 80% adherence is pretty good, but that’s the worst thing they could do with regard to resistance," MacArthur says. "They have to get 95% or 100% or more of doses prescribed."

Another important treatment strategy regarding drug resistance is to hold off using the latest new class of drugs until there are enough drugs in that class to form a multidrug regimen, he suggests.

"We’ve had [enfuvitide] out for several years, and it’s a very good drug and a new class, but we’ve been reluctant to use it by itself in patients with resistant virus because we’ve learned from past mistakes that adding one drug is not likely to lead to a good response," MacArthur adds. "We’re holding off on that drug until we have two active drugs to give at the same time."

The other good news about HIV drug resistance is researchers have developed new tools for clinicians to use in determining the best course of action when given a patient’s resistance profile.

"There are a lot of drug-resistance algorithms being developed," says Lisa Ross, a researcher with GlaxoSmithKline in Research Triangle Park, NC. "

I think the algorithms are getting better, and the way they improve over time is by researchers getting more information and publishing the data." Some drug-resistance algorithms look at biologic differences and some look at clinical differences, she notes.

"I think ideally the most predictive algorithms would be based on clinical outcomes, but sometimes it’s very difficult to get enough information that’s similar to put together that kind of conclusion," Ross adds.

"You have to start compiling data from a number of different studies to get a large enough number of patients, and then there are a number of variables that can be confounding."

Still, there are good scientists tackling this problem, and some of them offer their algorithms on the Internet, including Bob Shafer, whose work is available at http://hivdb.stanford.edu; and Ronan Bolume who works on predictive algorithms for the web site at www.ablsa.com, she says.

VircoLab Inc. of Durham, NC, also has developed new tools that will help clinicians understand resistance and avoid the further evolution of existing resistance, says Lee Bacheler, PhD, vice president of clinical virology for VircoLab.

"What we have been focusing on at VircoLab for several years now . . . is to try to define what is resistant and nonresistant based on how patients respond to a drug," she says.

"We’ve presented work from our project where we defined what we call clinical cutoffs,’ the levels of resistance at which a response to a drug begins to be lost, and the upper clinical cutoff beyond which the response to a drug is minimal," Bacheler says.

"We took the approach of defining such cut-offs for all drugs in a consistent manner," she adds.

"Other groups have tried to define clinical cut-offs for one drug or used one study to describe loss of function from baseline resistance, but we take the same methodology to all drugs."

Called the VircoTYPE HIV-1 test, it is designed to predict phenotypic resistance levels of a sample HIV-1 virus based on the viral genotype. It’s based on more than 13,000 patient records covering more than 3,150 treatment regimens, all of which are combination therapies.

"The cutoffs are individual and specific for each drug but are derived from a large data set in which we collected clinical response data from a large number of clinical collaborators," Bacheler says.

"We make a separate data set for each drug, and some of our preconditions were that we wanted to analyze response to combination therapy." While establishing a cutoff to monotherapy might produce a clinically clean result, it’s not relevant to how patients are treated today, she notes.

The algorithm was launched late in 2004 and soon should be posted on VircoLab’s web site, where the numbers are made available to the public, although they apply specifically to the VircoTYPE test.

"We’re hoping this really makes resistance testing results more relevant for clinicians and their patients," Bacheler says.

With this information, clinicians will easily know when a patient’s response to a drug indicates that it’s unlikely there will be any additional response to the drug and when the response is likely to be reduced or when the virus will be fully susceptible to the drug, she says.