Diagnostic tests for HIV resistance are created as quickly as the new drugs

Research is leading individualized medicine evolution

The lag between when new HIV drugs are developed and when resistance tests are available to clinicians for monitoring a patient's success on these medications soon will be nil.

Pharmaceutical companies and diagnostic labs have used rapid technological changes and collaborations to make it possible for screening tests to be available nearly as soon as new antiretroviral drugs are approved for the market.

"We were working with drug companies on what they needed for drug development before we had a patient testing service," says Bill Young, chairman and chief executive officer of Monogram Biosciences of South San Francisco, CA. Monogram formerly was ViroLogic Inc., and the company markets a variety of HIV assays, including PhenoSense GT, GeneSeq HIV, PhenoSense Entry, and Replication Capacity.

"We have been a customer and collaborator since the 1990s," Young says.

"Some companies are much more open with us, and some are a little less open," Young explains. "But the intent for both is to make sure we know what they're working on so the assays can be made during the development process."

Then, when the drug makes it to the market, the resistance tool is ready, as well, Young adds.

Pfizer Inc. had approached Monogram in 2002, asking the company for a collaboration that would be beneficial to both companies, Young recalls.

"The sooner you can get in lock-step with drug development, the more likely your technology will be in wide use when it's in the market," Young says.

Diagnostic labs have become more sophisticated in recent years, improving viral load assays and CD4 cell assays, as well as expanding choices in resistance testing, says Robert Grant, MD, an associate investigator at Gladstone Institute of Virology and Immunology in San Francisco and an associate professor of medicine at the University of California, San Francisco.

"Significant innovations have allowed labs to conduct those assays in an easier and more reliable manner," Grant says.

"Drug resistance testing has now become standard in many parts of the world," Grant adds. "They measure the presence of mutations in virus infection, and those mutations have been well characterized with respect to their relationship to drug resistance or failure of clinical/biologic response."

Monogram Biosciences is on the cutting edge of the new diagnostic technology.

The company has in development an assay for resistance to integrase inhibitors, which is the first step in optimizing a patient's background therapy, Young suggests.

Other companies also are developing assays for resistance to integrase inhibitors, he adds.

"Our big news will be studies done with two CCR5 inhibitors, and these are the most advanced, well into phase III," Young says.

At the XVI International AIDS Conference, held Aug. 13-18, 2006, in Toronto, Canada, Monogram investigators presented an abstract showing that the company's Co-Receptor Tropism assay is accurate, precise, sensitive, reproducible, and robust for the measurement of HIV-1 CRT.1

"With new drugs in the pipeline, the entry inhibitors, assembly inhibitors, the integrase class, we're extending our range of resistance tests," says Alfred Merriweather, chief financial officer of Monogram Biosciences.

"The driver for the changes is the new classes of drugs," Merriweather says. "There are 20 approved drugs and 60 or more in development."

The increasing complexity of the drugs coming to market will fuel the need for tests that help clinicians understand how these drugs will relate to a particular patient, Merriweather adds.

"With the CCR5 compounds, it potentially is breaking new ground in the sense that there's a potential for a class of drug in which the very prescription is dependent on a [lab] test," Merriweather says.

Resistance testing has evolved in the past decade from a new technological advance in HIV treatment to a standard of care in which resistance assays are used routinely to assess the consequences of HIV mutations and resistance to existing antiretrovirals.

As Integrase and entry inhibitors develop, we've had to develop assays that work in those settings as well," Young explains. "We work with drug companies during the development phase, and when the drug is marketed, the assays are ready to go and have affirmative data on them."

Monogram's Trofile assay, which is able to determine whether a patient's virus will gain entry into cells via the CCR5 and/or the CXCR4 co-receptors, has been used by Pfizer for all clinical studies involving the pharmaceutical company's investigational CCR5 antagonist, Young says.

"It's not just being used as a monitoring tool; it's being used to select patients," Young says. "It was actually developed and pre-evaluated three years ago."

Earlier this year, Monogram and Pfizer entered into a commercial agreement to make the assay commercially available internationally, Young adds.

"The other thing the assay can be used for, and the jury is still out on this, is whether you need to monitor patients after they're put on the drug or after they fail therapy," Young says.

CCR5 inhibitors may prove to be useful earlier in the course of HIV infection before alternative viruses can appear, Grant says.

"This is an area that's controversial right now," Grant says. "There are trials using the new drugs in a salvage capacity for people who have failed other drugs and may have later stage infection, but there's also a lot of interest in using them earlier in the course of HIV infection."

"I think that tropism assays may become part of standard medical care for any number of reasons," Grant says. "They will be used to predict resistance and the rate of progression, and they will be used to select which entry level inhibitors should be used."

Those are three possible indications that could emerge for tropism assays, and any one of these could become very important in the near future, making the assay a part of standard HIV care, Grant notes.

For integrase inhibitors, the drug resistance tests will be used similarly to current resistance tests, as soon as these are available, Grant says.

Another new area involves assays that can detect minor variance, which may be more predictive of whether resistance is present, Grant notes.

"These could be important for when people are starting antiviral therapy, especially in communities where they acquired the virus from a sexual partner," Grant says.

After the patient is off therapy due to treatment interruption or because they were only taking antiretrovirals during pregnancy and chose to stop when the baby was born, there might be drug resistance present that cannot be predicted in a standard assay, Grant says.

"There are a variety of minor variance assays in research labs, but not in clinical labs, but it's an area of innovation that we're starting to see," Grant explains. "They reliably can detect down to 1 percent of viral mutation, while normal assays detect more than 50 percent of mutations."

Another area of laboratory diagnostics that requires innovation has to do with using the laboratory in resource poor areas of the world, Grant says.

"I think there's a need for healthy skepticism about how useful and necessary laboratory resources are in management of HIV infection," Grant says. "In resource poor areas the lab testing costs more than the drug itself, and it's an open question of whether it's essential to have all the lab tests available for retroviral therapy."

Investigators now are looking at these issues through randomized studies, he adds.

The advantage resource poor areas have is that they are beginning antiretroviral therapies at a time when the drugs are more potent than ever, so this will reduce drug resistance. But the disadvantage is that their drug supply chain is vulnerable, so they'll see people going on and off therapy because of an imperfect drug supply, Grant explains.

"We really need studies to look directly at how much drug resistance there is in resource poor areas, and we need the appropriate technology to determine which tests are most useful and essential for them," Grant adds. "They cannot afford lab support that is not essential, and they need the most cost effective ways to conduct those tests."

Reference:

  1. Limoli K, et al. Technical Validation Defines the Performance of Monogram's HIV Co-Receptor Tropism Assay. Abstract presented at the XVI International AIDS Conference, held Aug. 13-18, 2006, in Toronto, Canada.