by Chael Needle

Innovations in resistance testing can mean better treatment strategies for the twenty-five to fifty percent of patients on HAART in the U.S. whose anti-HIV medications have failed them because of drug resistance. Virco, a Belgium-based company currently celebrating its tenth anniversary, is confident that its latest offering in the field of bioinformatics—the vircoTYPE HIV-1 resistance analysis with clinical cutoffs (CCOs)—will continue to expand treatment approaches for these patients, especially those who have switched regimens before.

If a particular combination of drugs is not suppressing viral load, patient and physician can check to see if drug resistance is part of the problem. If so, which drugs are rendered less effective? And how resistant to this drug has the virus become? Conventional testing often struggles to answer the second question.

Genotypic testing, for example, can identify particular resistance-causing mutations in a virus’s genome. With this information, physicians can use a set of rules to analyze resistance, albeit indirectly. Phenotypic testing obtains a direct measure of resistance, exposing viral isolates to increasing concentrations of individual drugs in the laboratory. While phenotypic testing can detect degrees of resistance and provide a quantitative measure of lower levels of resistance, this mode of testing is expensive and time-consuming. Another limitation is that phenotypic testing results are based on cutoffs, markers that show degrees of resistance, that are derived either from test tube analysis or from small pools of patient samples, both of which may provide only limited applicability to the patient whose resistance is being measured. For example, conventional phenotyping must rely on samples from different laboratories and different methodologies, which means the measurement of resistance is less refined and can be less accurate than vircoTYPE.

The vircoTYPE HIV-1 assay offers physicians reliable phenotypic results without many of the disadvantages associated with conventional testing. Its report offers highly accurate clinical cutoffs. Because these CCOs—derived from a large database of patients treated in clinical trials and patient cohort studies—represent a wide range of patients whose resistance was analyzed using a common methodology, the values are applicable to a broad range of patients. Another database of matched pairs of genotypes and phenotypes is used by the virtual phenotype engine to predict fold changes. “We’re overcoming some of the variability of the conventional assays by this wealth of information,” says David Rebey, Executive Director, Professional Affairs, Midwest Region, Virco. When a genotype of a patient’s blood sample arrives from a reference lab, Virco looks up similar mutational patterns on a drug-by-drug basis and phenotypes of each matching sample are retrieved. In others words, assays on these samples do not have to be run every time for every drug. The total turnaround time is greatly reduced.

The CCOs utilized by vircoTYPE also look at drugs as they are used in combination therapy; the conventional method looks at a drug’s resistance in isolation from other drugs with which it may be in combination. With vircoTYPE, resistance analysis becomes less abstract and closer to how resistance progresses in actual treatment regimens.

Resistance, reminds Rebey, is probably not an all-or-nothing quality: “The report provides two clinical cut-offs (for those drugs for which we have established clinical cut-offs): a lower clincial cut-off, at which point about twenty percent of the activity that would be expected with an individual drug against a wild-type virus is lost; and a higher clinical cut-off, at which point eighty percent or more of that drug’s activity is lost.” Understanding resistance as a continuum of a drug’s susceptibility to the virus allows vircoTYPE to report on the partial activity of drugs. Rebey says that measuring fold changes along a continuum allows the physician to look at how much activity is lost and provides more “granular” resistance information with which to identify more treatment options for patients, especially those with multidrug resistance.

Information on the report that many physicians are finding useful, adds Rebey, are the “separate clinical cut-offs for protease inhibitors used alone and when boosted with ritonavir. A lot of resistance can be overcome through pharmacokinetic enhancement, such as concomitant use of ritonavir. When ritonavir is used with PIs, the clinical cut-offs are higher than when the PIs are used alone.” Rebey says that while physicians have known for a long time that ritonavir enhancement helps overcome resistance, now they can begin to answer to what degree.

For more information about vircoTYPE HIV-1, log on to www.virco.be.

Chael Needle wrote about a new protease inhibitor, Aptivus, for the August issue.

September 2005