Phenotypic Drug resistance Testing: VIRA 3001

A randomized Trial Evaluating the Initial Response of Prospective Phenotypic Resistance Testing in Patients Experiencing Loss of Suppression on First PI Containing Regimen

Cal Cohen reported interim results for the VIRA Study team.

The study objective is to assess the virologic impact of prospective phenotypic resistance testing (PRT) using the Virco Antivirogram. Assay as compared to the standard of care (SOC), i.e. making treatment selection without assay. The study measured response on the proportion <400 copies/ml of plasma HIV-RNA at week 16, the change in viral load from baseline, and the CD4 change.

The study criteria included prior therapy with 2 or more NRTIs and 1 PI, plasma viral load >2000 copies/ml, stable antiretroviral therapy for >1 month prior to screening, willing to maintain current regimen until study Day 1, no prior phenotypic testing, NNRTI-naÔve, and enrollment period was April '98 to Sept '99.

Patients (n=144) were randomized to PRT or SOC (n=130). Patients were asked to plan a regimen they would give to the patient. This was done prior to receiving any phenotype results for those randomized to PRT arm. One week later the PRT were received by those randomized to that arm. At the next visit patient and doctor could redesign the regimen. Both of these regimens were recorded. At this point, 111 patients remained in the PRT arm, and 107 in the SOC arm. All but a few individuals reached week 16 for this analysis.

The baseline viral load was about 4 log (10,000 copies/ml) in each arm, about 33% in each arm had CDC defined AIDS, CD4s were about 350 in each arm.

Cumulative ART Experience at Screening (a few had taken RTV/SQV)

The individuals as a group with >4 fold IDV resistance had no sensitivity to IDV, 12% were susceptible to NFV, 70% to amprenavir, 60% to SQV, and 12% to RTV. The group who had >4 fold resistance to NFV-- 60% were sensitive to IDV, none to NFV, 90% to amprenavir, 80% to SQV, and 65% to RTV.

Regarding NRTIs, despite use of d47, despite prior use of d4T, ddI, and AZT over 70% were sensitive to those drugs. Only 20% retained sensitivity to 3TC, and 80% were sensitive to abacavir.

After receiving the Phenotypic Test results, 78% overall in the PRT arm altered the regimen those chose prior to receiving the test results: 63 changed their NRTIs, 49% changed their NNRTI, 57% changed their PI. In the SOC arm, where they did not receive Phenotypic test results 42% overall changed their regimen after the first selection but prior to starting study: NRTIs 35%, PI 32%, NNRTI 24%.

There was a trend towards 3 or more active drugs (77%) in the PRT arm and 62% in the SOC arm. An active drug is defined <4 fold resistance. A median number of 3.4 drugs were taken in each of the two arms.

They used an ITT analysis where those who did not yet reach 16 weeks were counted failures, but those who discontinued before study started were not included. Overall, 38% in the PRT arm had <400 copies/ml at week 16 while 22% had <400 in the SOC arm. When baseline RNA was <10,000 copies/ml 23% in the SOC arm had <400, and 43% had <400. When baseline HIV-RNA was 10,000-100,000 33% in the PRT arm had <400 and 26% in the SOC arm had <400. When baseline VL was >100,000 17% had <400 in the SOC arm and 38% had <400 in the PRT arm.

Using an observed analysis 58% in the PRT arm (n=72) had <400 copies/ml at week 16, while 37% had <400 copies/ml in the SOC arm (n=68) --p=0.011.

In the SOC arm, the viral load reduction from baseline to week 16 was -0.75 log, and -1.27 in the PRT arm (p=0.005). These results were found using the standard Roche Amplicor assay with 400 copies/ml being the cutoff for undetectable. The Ultra-sensitive assay is now being run.

So, what test should a person use--the genotype or the phenotype or both? It's suggested that in early failures the genotype is recommended but with additional failures it may be more difficult to understand the genotype results, and experts suggest using the phenotype. Considerations are the cost and reimbursement, and how long it takes to get the results back. The genotype is less costly than the phenotype. You have to be careful about which lab you send your blood sample to for testing. Some commercial labs are not expert in interpreting test results. A study found that there can be quite a bit of variability between labs in the results they report. As well, a certain amount of expertise is required in interpreting and applying the results by a doctor. Your doctor should consult with an expert for advise. I think the makers of these tests may offer the best source for quality assurance: Virco genotype and phenotype tests are available exclusively through LabCorp in the USA; Virologics genotypic test is available through VirolLogic Inc which is based in SF; and the Visible Genetics Inc genotype test is only available, at this point, through a study or by calling the Applied Sciences Lab in Norcross, GA. VGI is located in Toronto.